Advertisement

Protein & Cell

, Volume 9, Issue 2, pp 216–237 | Cite as

The emerging role and targetability of the TCA cycle in cancer metabolism

  • Nicole M. Anderson
  • Patrick Mucka
  • Joseph G. Kern
  • Hui FengEmail author
Open Access
Review

ABSTRACT

The tricarboxylic acid (TCA) cycle is a central route for oxidative phosphorylation in cells, and fulfills their bioenergetic, biosynthetic, and redox balance requirements. Despite early dogma that cancer cells bypass the TCA cycle and primarily utilize aerobic glycolysis, emerging evidence demonstrates that certain cancer cells, especially those with deregulated oncogene and tumor suppressor expression, rely heavily on the TCA cycle for energy production and macromolecule synthesis. As the field progresses, the importance of aberrant TCA cycle function in tumorigenesis and the potentials of applying small molecule inhibitors to perturb the enhanced cycle function for cancer treatment start to evolve. In this review, we summarize current knowledge about the fuels feeding the cycle, effects of oncogenes and tumor suppressors on fuel and cycle usage, common genetic alterations and deregulation of cycle enzymes, and potential therapeutic opportunities for targeting the TCA cycle in cancer cells. With the application of advanced technology and in vivo model organism studies, it is our hope that studies of this previously overlooked biochemical hub will provide fresh insights into cancer metabolism and tumorigenesis, subsequently revealing vulnerabilities for therapeutic interventions in various cancer types.

KEYWORDS

glutaminolysis the TCA cycle cancer metabolism glycolysis 

Introduction

Cancer is a disease characterized by the accumulation of genetic alterations and gene deregulations, resulting in uncontrolled cell proliferation that demands both increased energy production and macromolecule synthesis. To cope with increased metabolic stress, malignant cells often reprogram their biochemical pathways to enable rapid uptake and breakdown of nutrients, thus contributing to disease transformation, maintenance, and progression (Hanahan and Weinberg, 2011; Ward and Thompson, 2012). The birth of cancer metabolism research extends back to the early 20th century, when Otto Warburg noted the heavy dependence of cancer cells on glycolysis for growth (Warburg et al., 1927). Indeed, various types of cancer cells increase their glucose uptake and preferentially utilize glucose through aerobic glycolysis (Gillies and Gatenby, 2007; Pavlova and Thompson, 2016). This effect was subsequently applied in the clinic for tumor imaging and detection through positron emission tomography scans of radiolabeled glucose analogs (Papathanassiou et al., 2009). These early findings laid the groundwork for a recent revival of interest in cancer metabolism research, which has lead to discoveries showing overactivation and/or rewiring of multiple metabolic pathways in cancer cells. In just the last ten years, the significance of metabolic reprogramming has led to its inclusion with the classic hallmarks of cancer (Hanahan and Weinberg, 2011). Accumulating evidence indicates that exploiting the unique metabolic dependencies of tumor cells represents an exciting new direction of targeted therapy (Pathania et al., 2009; Kishton and Rathmell, 2015).

The tricarboxylic acid (TCA) cycle is a central hub for energy metabolism and macromolecule synthesis and redox balance. The cycle is composed of a series of biochemical reactions occurring in the mitochondrial matrix, which allow aerobic organisms to oxidize fuel sources and provide energy, macromolecules, and redox balance to the cell. Aberrant TCA cycle function is implicated in a wide variety of pathological processes. Genetic diseases with compromised TCA cycle function due to inherited cycle enzyme mutations, such as fumarase (FH) deficiency, are rare but severe (Rustin et al., 1997). Moreover, several TCA cycle enzymes are deregulated in obesity, including citrate synthase, which exhibits reduced activity in obese mice (Cummins et al., 2014). Multiple neurodegenerative disorders such as Alzheimer’s disease are associated with reduced activity of the α-ketoglutarate dehydrogenase complex (KGDHC) (Gibson et al., 2010). In light of the widely accepted belief that cancer cells primarily utilize aerobic glycolysis, the role of the TCA cycle in cancer metabolism and tumorigenesis has been overlooked until recently.

With the application of contemporary technology, such as unbiased and targeted metabolomics, as well as genetic and biochemical studies using animal models, many recent advances have been made in the field of cancer metabolism. Studies have demonstrated that tumor cells can indeed uncouple glycolysis from the TCA cycle, allowing the use of additional fuel sources such as glutamine to meet their heightened metabolic needs (Chen and Russo, 2012) (Pavlova and Thompson, 2016). Importantly, glutamine is now established as an important nutrient source across numerous cancer types, especially for MYC-driven cancers (DeBerardinis and Cheng, 2010). The role of lipid metabolism in tumorigenesis has also received increased attention in recent years. Altogether, these studies have provided convincing evidence to establish the role of the TCA cycle in cancer metabolism and tumorigenesis (Sajnani et al., 2017). Importantly, various oncogenes and tumor suppressors regulate both the uptake and breakdown of fuel sources in the TCA cycle by regulating the expression of fuel transporters and/or activity of cycle enzymes in cancer cells (Chen and Russo, 2012). Multiple cycle enzymes, including aconitase (also known as aconitate hydratase, AH), isocitrate dehydrogenase (IDH), FH, succinate dehydrogenase (SDH) and KGDHC, are frequently mutated or deregulated in human cancers (Eng et al., 2003; Juang, 2004; Yan et al., 2009). Recent results from clinical testing suggest that targeting reprogrammed metabolic pathways, including the TCA cycle, could provide a new and promising therapeutic avenue for the treatment of a broad spectrum of cancers.

Fuels feeding the TCA cycle

The TCA cycle serves as a convergence point in the cellular respiration machinery, which integrates multiple fuel sources derived from the diet including glucose, glutamine, and fatty acids. Through various biochemical reactions, the cycle produces intermediates for use as building blocks in macromolecule synthesis, as well as energy and electron acceptors that are utilized in downstream cellular processes such as the electron transport chain (ETC) reactions. Although both normal and tumor cells can catabolize all major types of fuels, they differ in the rate of uptake and catabolism of each fuel. While glucose provides the main source of pyruvate entering the TCA cycle in normal cells, cancer cells often shunt glucose away from the TCA cycle for catabolism through anaerobic glycolysis, and thus are more dependent on glutamine and fatty acids to replenish TCA cycle intermediates (Eagle, 1955).

Glucose

Glucose is imported into the cell by glucose transporters (GLUT) and serves as the most common fuel source in mammalian cells (Fig. 1). In normal cells, most cellular glucose enters the TCA cycle in the form of pyruvate, although glucose can also be utilized for lactate production or macromolecular synthesis through the pentose phosphate pathway (Fig. 1). Through glycolysis, one glucose molecule is converted into two pyruvate molecules, which are primarily oxidized to produce acetyl-CoA feeding the TCA cycle. Alternatively, under hypoxic conditions, pyruvate may be converted to lactate as well. Progression through the TCA cycle occurs when heightened energetic needs arise (Fig. 1). Glucose can also be synthesized through gluconeogenesis, a process reciprocally regulated compared to glycolysis in order to keep the metabolism of the cell efficient (Berg JM, 2002).
Figure 1

Transporters, fuels, enzymes, and biochemical reactions driving the TCA cycle. The typical input for the TCA cycle is acetyl-CoA, which is derived from pyruvate, the end product of glycolysis. Through a series of redox reactions, chemical bond energy from acetyl-CoA is harvested to produce high-energy electrons, which are carried to the electron transport chain by nicotinamide adenine dinucleotide (NAD+) and flavin adenine dinucleotide (FAD). Subsequent oxidative phosphorylation results in the production of adenosine triphosphate (ATP) from each acetyl-CoA. Because oxygen is required to regenerate NAD+ and FAD, the TCA cycle only proceeds in aerobic environments. There are a total of 8 steps in the TCA cycle, three of which are irreversible; the generation of citrate from oxaloacetate and acetyl-CoA by CS; the conversion of isocitrate to α-KG by IDH3; and the formation of succinyl-CoA from α-KG by KGDHC (Berg JM, 2002; Akram, 2014). The biochemical reactions in the TCA cycle are regulated by several means including substrate availability, product inhibition, and allosteric regulation, allowing the cell to control energy production based on its energy status (NADH/NAD+ ratio, ATP availability) and nutrient availability (Berg JM, 2002). Intermediates in the cycle can be derived from outside sources, such as the production of acetyl-CoA from β-oxidation of fatty acids or the production of α-KG from protein catabolism, particularly glutaminolysis (Houten and Wanders, 2010; Akram, 2014). Importantly, deregulation of TCA cycle enzymes, such as mutations and gene deregulations, or aberrant accumulation of TCA intermediates can have disease-relevant consequences. Proteins that are upregulated in cancer are highlighted as red and downregulated as blue, while enzymes mutated are marked with an asterisk. Abbreviations: CS: citrate synthase, AH: aconitase, IDH: isocitrate dehydrogenase, KGDHC: α-ketoglutarate dehydrogenase complex, OGDH: α-KG dehydrogenase, DLST: dihydrolipoamide S-succinyltransferase, DLD: dihydrolipoamide dehydrogenase, SCS: succinyl-CoA synthase, SDH: succinate dehydrogenase, FH: fumarate hydratase, MDH: malate dehydrogenase, PDH: pyruvate dehydrogenase, GLUT: glucose transporter, FATP: fatty acid transporter, SCL38A: sodium-coupled neutral amino acid transporter, ACLY: adenosine triphosphate citrate lyase, ACC: acetyl-CoA carboxylase, FAS: fatty acid synthase, GLS: glutaminase, GDH: glutamate dehydrogenase

Cancer cells markedly increase their glucose usage, as noted by Otto Warburg nearly 100 years ago. Tumors acquire additional glucose by upregulating the high-affinity glucose transporters GLUT1 and GLUT3, while simultaneously downregulating lower affinity transporters (Birnbaum et al., 1987; Baron-Delage et al., 1996). Not only do cancer cells increase the rate of glucose uptake and utilization, but the fate of imported glucose differs from that in normal cells as well. While normal cells and some cancer cells, such as lung cancer stem cells and leukemic cells, oxidize glucose in the mitochondria (Gatenby and Gillies, 2004; Gao et al., 2016; Kishton et al., 2016), most cancer cells preferentially break down glucose to produce lactate even in normoxic conditions (Kim et al., 2006), The process of aerobic glycolysis only generates 2 ATP per glucose molecule, a drastic reduction from 38 ATP when glucose is oxidized through the TCA cycle. To meet their heightened energetic needs, cancer cells turns to other fuel sources, such as glutamine, to feed the TCA cycle.

Glutamine

In addition to glucose, amino acids can also fuel the TCA cycle. Amino acids enter the cycle after being converted to either acetyl-CoA or α-keto acid intermediates: pyruvate, oxaloacetate, and succinyl-CoA (Berg JM, 2002). Glutamine is the most abundant amino acid in the human body, serving to transport nitrogen in the plasma for biosynthesis of non-essential amino acids, such as purines and pyrimidines, as well as fatty acids, or entering the TCA cycle in the form of α-ketoglutarate (α-KG) (Reitzer et al., 1979; Brosnan, 2003; Wang et al., 2017). Glutaminolysis, the breakdown of glutamine, is critical in replenishing cycle intermediates in proliferating cells. Glutamine is first hydrolyzed by glutaminase (GLS) to yield glutamate, which subsequently is either dehydrogenated by glutamate dehydrogenase (GLUD) to form α-KG or functions as a co-substrate for the transaminases, glutamate oxaloacetate transaminase and glutamate pyruvate transaminase to form alanine and aspartate respectively. α-KG is a substrate for oxidative decarboxylation by KGDHC or for reductive carboxylation by IDH2 (Mullen et al., 2011). Thus, glutaminolysis serves as a common pathway for both anaplerotic and cataplerotic processes.

The importance of glutaminolysis in cancer cell proliferation was noted decades ago by Harry Eagle, who found that HeLa cells preferred a molar excess of 10- to 100- fold of glutamine for maximum growth (Eagle, 1955). This metabolic dependence is partially driven by the glycolytic phenotype seen in certain types of cancer cells. Due to the excessive conversion of glucose to lactate, tumor cells use anaplerotic reactions to replenish TCA cycle intermediates, which is largely achieved through increased glutaminolysis (DeBerardinis et al., 2007). To do so, cancer cells upregulate both glutamine transporters and enzymes catalyzing glutaminolysis, thus uncoupling this pathway from growth factor-mediated stimuli (Fig. 1) (Pavlova and Thompson, 2016). The proto-oncogene MYC is a critical regulator of glutaminolysis and upregulates both glutamine transporters and GLS (Wise et al., 2008; Gao et al., 2009). Elevated levels of GLS and glutamine transporters enable tumor cells to derive large portions of their energy and macromolecules through glutamine catabolism, leading to glutamine addiction in numerous cancer types including myeloma and glioma (Bolzoni et al., 2016; Márquez et al., 2017).

Fatty acids

The third type of fuel source in cancer cells is fatty acids, which enter the TCA cycle after undergoing β-oxidation to generate acetyl-CoA. Acetyl-CoA is the substrate for both the fatty acid synthesis pathway and the TCA cycle, making lipogenesis an important convergence point for TCA cycle flux and cellular biosynthesis (Migita et al., 2008). In the process of β-oxidation, the acyl chain undergoes oxidation, introducing a double bond, followed by hydration to alcohol and oxidation to ketone. Finally, co-enzyme A cleaves the acyl tail to yield an acetyl-CoA and reduces the fatty acid chain length by two carbons. This process generates more acetyl-CoA per molecule than does either glucose or glutamine (Berg JM, 2002). De novo synthesis of fatty acids is critical to supply lipids for cell membrane formation in rapidly proliferating cells, and is regulated by fatty acid biosynthetic enzymes: adenosine triphosphate citrate lyase (ACLY), acetyl-CoA carboxylase (ACC), and fatty acid synthase (FAS). ACLY converts citrate to oxaloacetate and cytosolic acetyl-CoA. This cytosolic acetyl-CoA is carboxylated by ACC to form malonyl-CoA, which is then combined with additional acetyl-CoA until the 16-carbon unsaturated fatty acid palmitate is formed. Palmitate can then be modified to form additional required components of cell membrane.

While enzymes regulating lipid synthesis are often expressed in low levels in most normal tissue (Clarke, 1993), they are overexpressed in multiple types of cancers. ACLY is overexpressed in non-small cell lung cancer, breast cancer, and cervical cancer among others (Migita et al., 2008; Xin et al., 2016; Wang et al., 2017). ACC is upregulated in non-small cell lung cancer and hepatocellular carcinoma (Wang et al., 2016; Svensson and Shaw, 2017). FAS is overexpressed in prostate and breast cancers (Swinnen et al., 2002; Menendez et al., 2004). In tumor cells where the demand is much greater, lipogenesis occurs via these overexpressed enzymes. The increased activation and overexpression of these enzymes in tumors correlates with disease progression, poor prognosis, and is being investigated as a potential biomarker of metastasis (Xin et al., 2016).

Oncogenes and tumor suppressors impinging on the TCA cycle

Genetic alterations and/or deregulations of tumor suppressors or oncogenes often drive metabolic reprograming in cancers, although this effect can differ based on specific alterations or deregulations, and is often context-dependent. Several oncogenes, including MYC, HIF, P53, and RAS, are known to regulate the metabolic phenotype of tumors and play a critical role in determining how the TCA cycle is utilized in these cancer cells.

MYC

The proto-oncogene MYC controls a wide range of cellular processes, including cell proliferation, metabolism, cellular differentiation and genomic instability, and is a dominant driver of tumor transformation and progression (Meyer and Penn, 2008). Aberrant MYC activity, resulting from chromosomal translocations, gene amplifications or increased mRNA/protein stability, is found in over half of all human cancers (Gabay et al., 2014). Importantly, MYC is a central regulator of cellular metabolism, and can promote a broad range of metabolic pathways, such as aerobic glycolysis, glutaminolysis, mitochondrial biogenesis, oxidative phosphorylation, and nucleotide and amino acid biosynthesis (Adhikary and Eilers, 2005; Gabay et al., 2014; Wahlstrom and Henriksson, 2015). As stated early in this review article, MYC transcriptionally activates key genes and enzymes regulating glutaminolysis, and serves as the principal driver of glutamine metabolism through the TCA cycle (i.e., glutamine anaplerosis). Specifically, to promote the import of glutamine into the cell, MYC transcriptionally upregulates glutamine transporters ASC amino acid transporter 2 (ASCT2) and system N transporter (SN2). Additionally, Gao et al. demonstrated that MYC controls the conversion of glutamine to glutamate by activating glutaminase 1 (GLS1) through transcriptional suppression of its negative regulator miR-23a/b (Wise et al., 2008; Gao et al., 2009). There are two independent pathways that control the conversion of glutamate to α-KG entering the TCA cycle: one controlled by GLUD and another by aminotransferases. MYC-dependent cancer cells can utilize either GLUD or aminotransferases to convert glutamine to α-KG for the TCA cycle (Wise et al., 2008; Wang et al., 2011). MYC may also play a role in directing fatty acid oxidation and directing its metabolites into the TCA cycle by way of acetyl-CoA. Specifically, MYC expression leads to the upregulation of fatty acid transporters (e.g., fatty acid-binding protein 4) and fatty acid oxidation genes such as hydroxyacyl-CoA dehydrogenase (Wang et al., 2011; Edmunds et al., 2015).

HIF

Hypoxia-inducible factors (HIFs) are transcription factors that respond to reduced oxygen availability. HIFs are heterodimers composed of an oxygen-dependent α-subunit and a constitutively expressed β-subunit. Under normoxia, the α-subunit is targeted for degradation upon hydroxylation by prolyl hydroxylases (PHD) and subsequent ubiquitination by von Hippel-Lindau (VHL) tumor suppressor. Tumors activate HIFα either in the face of hypoxia resulting from poor vascularization or due to genetic abrogation such as VHL loss (Gordan and Simon, 2007). HIF activation orchestrates a metabolic program that promotes the catabolism of glucose through aerobic glycolysis and thus shifts glucose away from the TCA cycle (Semenza, 2012). HIF promotes glycolysis and lactate production through transcriptional upregulation of glucose transporters (SLC2A1 and SLC2A3), glycolytic enzymes (e.g., hexokinase (HK) and pyruvate kinase (PK)), and lactate dehydrogenase A (LDHA) (Kim et al., 2006). Kim et al. demonstrated that HIF1 suppresses glucose metabolism through the TCA cycle (i.e., glucose anaplerosis) by directly activating pyruvate dehydrogenase kinase 1 (PDK-1), a negative regulator of cycle enzyme pyruvate dehydrogenase (PDH) (Kim et al., 2006). To compensate for the reduction of glucose feeding the TCA cycle, tumor cells with HIF activation often increase the usage of glutamine (Le et al., 2012). Under hypoxia conditions, glutamine largely fuels the TCA cycle in the form of α-KG to promote reductive carboxylation that produces citrate for lipogenesis (Wise et al., 2008; Metallo et al., 2011; Gameiro et al., 2013).

P53

P53 is a transcription factor and known tumor suppressor that regulates many important cellular pathways, including cell survival, DNA repair, apoptosis, and senescence (Bensaad et al., 2009). Wild-type P53 plays an important role in metabolism by striking a balance between bioenergetics and biosynthesis. One of the ways it does so is by lowering rates of glycolysis and promoting oxidative phosphorylation. P53 acts to suppress glycolysis by directly downregulating glucose transporters (GLUT1 and GLUT4) and indirectly inhibiting the activity of glycolytic enzymes, phosphofructokinase 1 (PFK1) and phosphoglycerate mutase (Kondoh et al., 2005; Bensaad et al., 2006, 2009; Zhang et al., 2013). To promote oxidative phosphorylation, P53 ensures availability of anapleurotic substrates, glucose, and glutamine, to the TCA cycle. As an activator of PDH, P53 downregulates PDH’s negative regulator PDK2 and indirectly activates PDHA1 (PDH A1 subunit). Additionally, P53 promotes glutamine incorporation into the TCA through direct transcriptional upregulation of glutaminase 2 (GLS2) (Zhang et al., 2011; Contractor and Harris, 2012). In solid tumors, P53 is commonly mutated and somatic mutations of P53 occur in more than 50% of human malignancies (Kruiswijk et al., 2015). Subsequently, loss of wild-type P53 function has a significant impact on cellular metabolism, leading to enhanced glycolysis and repressed oxidative phosphorylation in these tumor cells.

RAS

The most frequently mutated RAS subfamily genes in cancer are KRAS, NRAS, and HRAS, which serve as intercellular signaling molecules to transduce extracellular signaling from receptor tyrosine kinase to downstream effectors (Pylayeva-Gupta et al., 2011; Stephen et al., 2014). RAS plays a critical role in activating scavenging pathways in certain types of tumors and promotes nutrient uptake through both the extracellular and intracellular sources (Pylayeva-Gupta et al., 2011; Stephen et al., 2014). For example, Kamphorst et al. demonstrated that KRAS-driven pancreatic cells scavenge proteins, such as glutamine, from the extracellular space and utilize them to fuel the TCA cycle (Kamphorst et al., 2015). Additionally, it has been shown that KRAS-driven non-small cell lung cancer cells utilize autophagy to access intracellular supplies of glutamine to promote TCA cycle function (Guo et al., 2011; Strohecker and White, 2014). Moreover, KRAS-driven cancer cells can scavenge branch chain amino acids (i.e., isoleucine, valine, and leucine) and convert them into acetyl-CoA to fuel the TCA cycle (Mayers et al., 2014). A recent study by Kerr et al. demonstrated that copy number gain of mutant KRAS associated with tumor progression can promote glucose anaplerosis to fuel the TCA cycle (Kerr et al., 2016).

Cycle enzyme alterations in cancer

The biochemical reactions in the TCA cycle are catalyzed by a number of enzymes. Recent findings show that multiple cycle enzymes are either mutated or deregulated in a broad spectrum of cancer, resulting in characteristic metabolic and epigenetic changes that are correlated with disease transformation and progression.

SDH

Succinate dehydrogenase (SDH), also known as complex II, has roles in the TCA cycle and the ETC. SDH is a heterotetrameric enzyme complex composed of 4 subunits (SDHA, SDHB, SDHC, and SDHD), which catalyzes the oxidation of succinate to fumarate in the TCA cycle, while simultaneously reducing ubiquinone to ubiquinol in the ETC (Chandel, 2015). Mutations in SDHA, SDHB, SDHC, SDHD and SDH assembly factor 2 (SDHAF2) have been identified in hereditary paragangliomas (hPGLs) and pheochromocytomas (PCCs) (Table 1) (Baysal et al., 2000; Niemann and Muller, 2000; Astuti et al., 2001; Baysal et al., 2002; Hao et al., 2009; Bayley et al., 2010; Burnichon et al., 2010). Heterozygous mutations in SDH predispose patients to hPGL and PCC. Loss of heterozygosity as a result of a second mutation in the wild-type SDH allele triggers neoplastic transformation; thus, SDH is classified as a tumor suppressor gene (Gottlieb and Tomlinson, 2005). Additionally, mutations in SDH have also been identified in gastrointestinal stromal tumors, renal tumors, thyroid tumors, neuroblastoma, and testicular seminoma, implicating its importance in a wide range of cancer (Bardella et al., 2011).
Table 1

Summary of cycle enzyme genetic alterations in cancer

Gene

Genetic alterations

Tumor context

Consequence of

alterations

References

SDHA

c.91C>T

c.1765C>T

c.212G>A

c.674C>T, c.818C>T

c.341A>G

c.367C>A

c.441delG

c.725_736del

c.989_9990insTA

c.1753C>T

c.1865G>A

c.1873C>T

c.1886A>T

Paragangliomas

Pheochromocytomas

Leads to reduction or loss of enzymatic activity of the SDH catalytic subunit and defective function of mitochondrial complex II

(Burnichon et al., 2010; Bardella et al., 2011; Korpershoek et al., 2011; Dwight et al., 2013; Evenepoel et al., 2015; Pillai et al., 2017)

c.2T>C

c.91C>T

c.113A>T

c.160C>T

c. 206C>T

c.224G>A

c.244A>T

c.T273I

c.457-3 457-1delCAG

c.457-2 c457delCAG

c.511C>T

c.553C>T

c.562C>T

c.688delG

c.767C>T

c.778G>A

c.800C>T

c.818C>T

c.985C>T

c.1043-1055del

c.1046 147delTG

c.1151C>G

c.1255G>A

c.1334C>T

c.1357G>A

c.1361C>A

c.1471G>T

c.1534C>T

c.1690G>A

c.1765C>T

c.1766G>A

c.1794G>C

c.1795-1G>T

c.1873C>T

c.1969G>A

Gastrointestinal stromal tumors

(Pantaleo et al., 2011; Italiano et al., 2012; Belinsky et al., 2013a; Belinsky et al., 2013b; Miettinen et al., 2013; Oudijk et al., 2013; Miettinen and Lasota, 2014; Evenepoel et al., 2015; Jiang et al., 2015)

c.2T>C

Renal cell carcinoma

(Jiang et al., 2015)

SDHB

c.-1- ?_72+ ?del

c.-1- ?_765+ ?del

c.3G>A

c.21delC

c.49delA

c.72+1G>A

c.73_76delGCCT

c.79C>A

c.136C>G

c.137G>A

c.141G>A

c.155delC

c.166-170delCCTCA

c.203G>A

c.213C>T

c.221insCCAG

c.238A>G

c.268C>T

c.269G>A

c.270C>G

c.271G>A

c.277T>C

c.287-2A>G

c.287- ?_540+ ?del

c.291G>A

c.293G>A

c.299C>T

c.300-4delCCTCA

c.300T>C

c.312insCACTGCA

c.328C>T

c.394T>C

c.402C>T

c.416T>C

c.421-2A>G

c.423+1G>A

c.438G>A

c.540G>A

c.541-2A>G

c.549_552delTACinsATACAG

c.557G>A

c.558-3C>G

c.566G>A

c.589C>T

c.649C>T

c.650G>T

c.653G>A

c.688C>T

c.689G>A

c.689G>T

c.708T>C

c.718_719delCT

c.721G>A

c.724C>G

c.724C>A

c.724C>T

c.725G>A

c.736A>T

c.761C>T

c.765+1G>A

c.778G>C

c.780delG

c.847delTCTC

c.859G>A

c.881C>A

c.889+1G>A

Paraganglioma

Pheochromocytoma

Reduces SDH catalytic activity and causes defects in enzymatic activity in mitochondrial complex II

(Neumann et al., 2004, 2009; Bardella et al., 2011; Sjursen et al., 2013; Evenepoel et al., 2015; Bennedbaek et al., 2016)

c.32G>A

c.88delC

c.136C>T

c.137G>A

c.847-50delTCTC

Renal cell carcinoma

(Vanharanta et al., 2004; Ricketts et al., 2008; Paik et al., 2014)

c.392delC

Thyroid carcinoma

(Zantour et al., 2004)

IVS1+1G>T

c.17_dup26GTCG{dup26}GCCA

c.17 42dup

c.43+1C>T

c.45_46insCC

c.72+1G>T

c.137G>A

c.274T>A

c.380T>G

c.423+1G>C

c.423+1G>A

c.423+20T>A

c.600G>T

c.725G>A

Gastrointestinal stromal tumors

(McWhinney et al., 2007; Pasini et al., 2008; Janeway et al., 2011; Miettinen et al., 2013; Miettinen and Lasota, 2014)

c.418G>T

Neuroblastoma

(Schimke et al., 2010)

c.587G>A

Pituitary carcinoma

(Tufton et al., 2017)

c.136C>T

T-cell acute leukemia

(Baysal, 2007)

SDHC

c.1A>G

c.2T>A

c.3G>A

c.23dupA

c.39C>A

c.43C>T

c.77 + 4760A>G

c.78-2A>G

c.78-19C>T

c.112A>G

c.126G>A

c.140-5527C>A

c.148C>T

c.166A>T

c.173T>C

c.191_207del17

c.210C>G

c.214C>T

c.218insA

c.224G>A

c.242G>T

c.242-5580C>A, c.212C>A

c.253_255dupTTT

c.397C>T

c.405+1G>T

c.439C>T

c.496C>G

IVS4+1G>A

Paraganglioma

Pheochromocytoma

Leads to reduced SDH enzymatic activity and defective function in mitochondrial complex II

(Douwes Dekker et al., 2003; Mannelli et al., 2007; Peczkowska et al., 2008; Neumann et al., 2009; Bennedbaek et al., 2016; Pillai et al., 2017)

IVS5+1G>A

c.1A>G

c.6delT

c.43C>T

c.57delG

c.224G>A

c.301delT

c.380A>G

c.397C>T

c.405+1G>A

c.455G>C

Gastrointestinal stromal tumors

(McWhinney et al., 2007; Pasini et al., 2008; Janeway et al., 2011; Miettinen et al., 2013; Miettinen and Lasota, 2014)

SDHD

c.2T>A

c.3G>C

c.14G>A

c.33C>A

c.33C>T

c.34G>A

c.36_37delTG

c.49C>T

c.50G>T

c.52+2T>G

c.53-2A>G

c.53+2T>G

c.55dupT

c.64C>T

c.106C>T

c.112C>T

c.118A>G

c.120_ 127delCCCAGAAT

c.129G>A

c.149A>G

c.168_169delTT

c.169 + 5G>A, c.53-889G>A

c.170-1G>T

c.184_185insTC

c.191_192delTC

c.204-216del13bp

c.206_218del13bp

c.208A>G

c.230T>G

c.233_242del10bp

c.242C>T

c.252T>G

c.274G>T

c.276_278delCTA

c.284T>C

c.302T>C

c.314+1G>C

c.317delG

c.325C>T

c.334_337delACTG

c.337_340delGACT

c.341A>G

c.341_342delAT

c.361C>T

c.367G>A

c.370delG

c.386_387insT

c.408delT

c.416T>C

c.441delG

c.443G>T

IVS1+2T>G

Paraganglioma

Pheochromocytoma

Reduces efficacy of SDH and impairs mitochondrial complex II activity

(Gimm et al., 2000; Taschner et al., 2001; Dannenberg et al., 2002; Douwes Dekker et al., 2003; Lee et al., 2003; Neumann et al., 2004; Simi et al., 2005; Galera-Ruiz et al., 2008; Neumann et al., 2009; Evenepoel et al., 2015; Bennedbaek et al., 2016; Pillai et al., 2017)

c.34G>A

c.57delG

c.352delG

c.416T>C

Gastrointestinal stromal tumors

(Pasini et al., 2008; Janeway et al., 2011; Miettinen et al., 2013; Oudijk et al., 2013; Miettinen and Lasota, 2014)

c.129G>A

Testicular seminoma

(Galera-Ruiz et al., 2008; Evenepoel et al., 2015)

SDHAF2

c.68C>T

c.139A>G

c.232 G>A

Paraganglioma

Pheochromocytoma

Leads to loss of flavination of SDH, reducing stability and activity of the enzyme complex

(Hao et al., 2009; Bayley et al., 2010; Pillai et al., 2017)

FH

p.Gln4X

1-bp del. In codon 17

p.Arg58X

p.Asn64Thr

p.Ala74Pro

p.His137Arg

p.Gln142Arg

2-bp del. In codon 181

Lys187Arg

Lys del. In codon 187

Arg190His

-15 splice site

p.Gly239Val

p.Arg300X

1-bp del. In codon 507

Multiple leiomyomatosis

Leads to loss of FH enzymatic activity and accumulation of fumarate in the cell

(Tomlinson et al., 2002)

c.1?_c.*100del

c.1?_404+?del

c.111insA

c.127_128delGA

c.138+1_138+10del10

c.147delT

c.157G>T

c.172C>T

c.191A>C

c.220G>C

c.233del

c.247_249+1delGAGGinsA

c.250-2A>G

c.266T>C

c.298delA

c.305C>G

c.349A>G

c.410A>G

c.425A>G

c.431C>T

c.434A>G

c.455T>C

c.503T>C

c.560A>G

c.568C>T

c.568delAC

c.569G>A

c.569G>T

c.575A>G

c.632A>G

c.666delC

c.698G>A

c.780delGC

c.782-788 7-bp del.

c.806T>C

c.808G>T

c.810delA

c.815T>C

c.821C>T

c.823C>T

c.824G>A

c.836T>A

c.869G>A

c.875T>C

c.891T>A

c.898C>T

c.952C>T

c.964A>G

c.968G>A

c.989A>G

c.1002T>G

2-bp ins @1004

c.1020T>A

c.1025C>A

c.1028A>G

c.1060G>A

c.1083-1086delTGAA

c.1108-2A>G

c.1121-1123 del TAC

c.1123delA

c.1126T>C

c.1138insA

c.1144A>G

c.1162delA

c.1187A>C

c.1189G>A

c.1210G>T

c.1234del

c.1265A>G

8-bp dup @ 1300-1307

c.1339delG

c.1349-1352delATGA

c.1371G>A

c.1431insAAA

Hereditary leiomymatosis and renal cell carcinoma

(Toro et al., 2003; Wei et al., 2006; Pfaffenroth and Linehan, 2008; Gardie et al., 2011; Smit et al., 2011; Chen et al., 2014; Wong et al., 2014; Arenas Valencia et al., 2017)

c.220G>C

c.426+1G>A

c.988A>G

c.994delA

Type 2 papillary renal cell carcinoma

(Gardie et al., 2011)

c.1394G>A

c.352A>C

Leydig cell tumors (Carvajal-Carmona et al.)

(Carvajal-Carmona et al., 2006)

435insAAA

691G>A

Ovarian mucinous cystadenoma

(Ylisaukko-oja et al., 2006)

IDH1

p.Arg100Gln

p.Arg132His

p.Arg132Cys

p.Arg132Ser

p.Arg132Leu

p.Arg132Gly

Gliomas/Glioblastomas

Increases affinity for NADPH/α-KG; reduces affinity for isocitrate; increases production of 2-HG

(Parsons et al., 2008; Dang et al., 2009; Yan et al., 2009; Pusch et al., 2011)

p.Arg132His

p.Arg132Cys

p.Arg132Ser

p.Arg132Gly

p.Arg132Leu

Acute myeloid leukemia

(Mardis et al., 2009; Abbas et al., 2010; Bayley et al., 2010)

p.Arg132Cys

p.Arg132Leu

p.Arg132Gly

p.Arg132Ser

Myelodysplastic syndromes/ Myeloproliferative neoplasms

(Kosmider et al., 2010; Pardanani et al., 2010)

p.Arg132Cys

p.Arg132His

p.Arg132Leu

p.Arg132Ser

Chondrosarcoma

(Amary et al., 2011)

p.Arg132His

p.Arg132Gly

p.Arg132Ser

p.Arg132Cys

Acute lymphoblastic leukemia

(Kang et al., 2009; Zhang et al., 2012)

p.Gly70Asp

p.Val71Ile

p.Gly105Gly; p.Val1781Ile

p.Gly123Arg

p.Ile130Met

p.His133Gln

p.Ala134Asp

Thyroid carcinoma

(Hemerly et al., 2010; Murugan et al., 2010)

p.Arg132Cys

p.Arg132His

Prostate carcinoma

(Kang et al., 2009; Ghiam et al., 2012)

IDH2

p.Arg172Gly

p.Arg172Met

p.Arg172Lys

Gliomas/Glioblastomas

Increases affinity for NADPH/α-KG; reduces affinity for isocitrate; increases production of 2-HG

(Yan et al., 2009)

p.Arg140Gln

p.Arg172Lys

p.Arg172Gln

p.Arg172Thr

p.Arg172Gly

Angioimmunoblastic T-cell lymphoma

(Cairns et al., 2012; Lemonnier et al., 2016)

p.Arg140Gln

p.Arg140Trp

p.Arg172Lys

p.Arg172Met

Acute myeloid leukemia

(Abbas et al., 2010; Gross et al., 2010; Pardanani et al., 2010)

p.Arg140Gln

p.Arg140Leu

Myelodysplastic syndromes/ Myeloproliferative neoplasms

(Kosmider et al., 2010; Pardanani et al., 2010)

p.Arg172Ser

Chondrosarcoma

(Amary et al., 2011)

FH

Fumarate hydratase (FH) is a homotetrameric cycle enzyme that catalyzes the stereospecific and reversible hydration of fumarate to L-malate. Beyond its mitochondrial role, FH is also expressed in the cytoplasm where it participates in the urea cycle as well as nucleotide and amino acid metabolism (Adam, 2014 #160). Heterozygous mutations in FH predispose patients to multiple cutaneous and uterine leiomyomas (MCUL), as well as hereditary leiomyomatosis and renal cell cancer (HLRCC) (Table 1) (Launonen et al., 2001; Tomlinson et al., 2002). Additionally, mutations in FH have been identified in bladder, breast and testicular cancer (Table 1) (Carvajal-Carmona et al., 2006; Ylisaukko-oja et al., 2006). Mutations predisposing patients to MCUL or HLRCC occur across the gene and include missense, frameshift, nonsense and large deletions at the FH locus (Table 1) (Bensaad et al., 2006). Similar to SDH, the enzymatic activity of FH is completely absent in HLRCC patients due to a loss of the remaining wild-type allele (Wei et al., 2006).

IDH

The IDH family is comprised of three isoforms (IDH1, IDH2, and IDH3) that convert isocitrate to α-KG. Only IDH2 and 3 are expressed in the mitochondria, while IDH1 is expressed in the cytoplasm. IDH1 and IDH2 function as homodimers that catalyze the conversion of α-KG to isocitrate and require NADP+ as a co-factor, whereas IDH3 is a heterodimer (IDH3A, IDH3B, and IDH3G) that can only oxidize isocitrate to α-KG and requires NAD+ as a co-factor (Chandel, 2015). Unlike FH and SDH, mutations in IDH1 and 2 are somatic heterozygous missense mutations that occur primarily at the active arginine residues that are critical for isocitrate binding (IDH1: R132; IDH2: R172, R140; Table 1) (Parsons et al., 2008; Dang et al., 2009; Mardis et al., 2009; Yan et al., 2009). No mutations in IDH3 have been reported so far. IDH1/2 mutations occur frequently in low-grade glioma and secondary glioblastoma (~80%), but can also occur in acute myeloid leukemia (20%), angioimmunoblastic T-cell lymphomas (20%), and rarely in other malignancies such as thyroid, colorectal, and prostate cancer (Table 1) (Kang et al., 2009; Yen et al., 2010; Ghiam et al., 2012; Ohgaki and Kleihues, 2013; Yen et al., 2017). These neomorphic mutations result in the gained function of converting α-KG to 2-hydroxyglutarate (2-HG), an oncometabolite.

Deregulation of other cycle enzymes

Beyond mutations detected for cycle enzymes, several studies have demonstrated that other cycle enzymes, CS, AH, and KGDHC, are deregulated in cancer. CS catalyzes a rate-limiting step in the TCA cycle and is either overexpressed or has increased enzymatic activity in pancreatic, ovarian, and renal cancer (Schlichtholz et al., 2005; Lin et al., 2012; Chen et al., 2014). AH is a reversible enzyme that catalyzes the conversion of citrate to isocitrate and its expression is downregulated in both gastric and prostate cancer (Singh et al., 2006; Wang et al., 2013). KGDHC is a rate-limiting enzyme of the TCA cycle and has three components including α-KG dehydrogenase (OGDH), dihydrolipoamide S-succinyltransferase (DLST), and dihydrolipoamide dehydrogenase (DLD). OGDH is downregulated in colorectal cancer as the result of promoter hypermethylation and similar promoter hypermethylation has been documented in breast, lung, esophageal, cervical, and pancreatic cancer (Hoque et al., 2008; Ostrow et al., 2009; Fedorova et al., 2015). Interestingly, Snezhkina and colleagues have demonstrated that an alternative splice variant of OGDH that is tumor specific is overexpressed in colorectal cancer (Snezhkina et al., 2016). OGDH is regulated by Ca2+, adenine nucleotides, and NADH, and the tumor-specific isoform lacks three regions of the protein and exhibits reduced sensitivity to Ca2+. Additionally, Anderson et al. found that the E2 component of KGDHC, DLST, is upregulated in T-cell acute lymphoblastic leukemia (T-ALL) (Anderson et al., 2016).

Disease mechanisms underlying cycle enzyme alterations

Genetic alterations can occur in multiple cycle enzymes; however, their mechanisms of action in tumorigenesis differ. Both SDH and FH are classical tumor suppressor genes, and predispose individuals with heritable mutated genes to cancer when the second wild-type allele is lost (Chandel, 2015). Inactivating mutations in FH result in a build-up of fumarate and metabolic reprograming (Pollard et al., 2005), which includes an increased dependence on glycolysis and glutamine anaplerosis (Aspuria et al., 2014). In tumor cells harboring mutant FH, an accumulation of fumarate results in succination of cysteine-modifying proteins such as kelch-like ECH-associated protein 1 (KEAP1) and mitochondrial aconitase (ACO2) (Yang et al., 2014). Loss-of-function mutations of SDH result in the accumulation of millimolar concentrations of succinate and reduced levels of fumarate and malate (Pollard et al., 2005), which lead to disruption of multiple metabolic pathways including central carbon metabolism (Yang et al., 2013; Aspuria et al., 2014). On the other hand, IDH1/2 missense mutations render the enzymes acquiring neomorphic activity that can convert α-KG to 2-HG (Dang et al., 2009). 2-HG is an oncometabolite that acts as a competitive inhibitor to α-KG-dependent dioxygenases, such as hypoxia-inducible factor (HIF), prolyl hydroxylases (PDHs), JmjC domain-containing histone demethylases, and ten-eleven translocation (TET) family of 5mC DNA hydroxylases (Chowdhury et al., 2011; Xu et al., 2011; Koivunen et al., 2012). The inhibition of these dioxygenases results in broad epigenomic alterations that both suppress differentiation and promote proliferation. Mutations in IDH2, FH, and SDH share a common mechanism of inhibiting α-KG-dependent dioxygenases through 2-HG, fumarate, or succinate, respectively (Hoekstra et al., 2015). Both FH and SDH mutations induce a state of pseudohypoxia, where 2-HG, fumarate or succinate can inhibit PHDs, resulting in stabilization of HIF. Additionally, mutations of FH, SDH, and IDH1/2 cause increased production of reactive oxygen species (ROS), either directly by mutated SDH or indirectly in tumor cells with mutant IDH1/2 and FH (Hoekstra et al., 2015). For example, glioma cells with IDH mutations have increased ROS and reduced GSH levels due to insufficient NADPH pools (Shi et al., 2015). In cancer cells with FH mutations, the accumulation of fumarate results in elevated levels of succinic-glutathione (GSF), which acts as an alternative substrate for GSH reductase, ultimately leading to decreased levels of NADPH and GSH (Sullivan et al., 2013).

Potential approaches to target the TCA cycle

Therapeutically targeting the TCA cycle function in cancer is an attractive strategy to treat cancer and two strategies are currently being tested in the clinic. Many tumors utilize glutamine as a fuel source for the TCA cycle, thus suppression of glutaminolysis through small molecule inhibitors is an attractive approach to therapeutically target these tumors (Seltzer et al., 2010; Cheng et al., 2011; Le et al., 2012; Yuneva et al., 2012; Gameiro et al., 2013). An initial strategy utilized glutamine analogues, such as 6-diazo-5-oxo-L-norleucine, to target glutaminolysis (Ovejera et al., 1979; Ahluwalia et al., 1990; Griffiths et al., 1993). While these compounds highlight the potential of targeting glutamine anaplerosis, they ultimately failed to enter clinics due to high tissue toxicities. Additional studies have demonstrated that glutamine limitation, through either depletion of glutamine in the plasma (L-aspariginase) or blocking glutamine transport (sulfasalazine), can provide therapeutic benefit (Oettgen et al., 1967; Lo et al., 2008; Chan et al., 2014; Parmentier et al., 2015; Rodman et al., 2016; Roh et al., 2016; Shitara et al., 2017). Recently, GLS inhibitors, such as CB-839, an orally available, potent, and specific inhibitor of GLS, have shown anti-tumor efficacy. CB-839 disrupts the conversion of glutamine to glutamate and alters a number of downstream pathways, including the TCA cycle, glutathione production, and amino acid synthesis (Gross et al., 2010; Jacque et al., 2015). Phase I clinical trials are currently underway for CB-839, and examine its effectiveness for the treatment of both hematological malignancies and solid tumors (NCT02071927 and NCT02071888).

Besides targeting glutaminolysis outside the TCA cycle through GLS inhibition, several recent studies indicate that KGDHC represents a striking vulnerability for numerous cancers, and is a promising therapeutic target. Utilizing a MYC-driven model of T-ALL, Anderson and colleagues demonstrated that heterozygous inactivation of DLST (the E2 enzyme of KGDHC) was sufficient to significantly delay tumor onset without impacting normal animal development (Anderson et al., 2016). Additionally, they show that DLST inactivation in T-ALL cells disrupts the TCA cycle, while slowing cell growth and inducing apoptosis (Anderson et al., 2016). Allen et al. conducted a focused siRNA screen on TCA cycle enzymes, and found that many cancer cells highly depend on OGDH (the E1 component of KGDHC) for growth and survival (Allen et al., 2016). A recent study by Ilic et al. demonstrated that cancer cells harboring oncogenic PI3K mutations require all three components of KGDHC, OGDH in particular, for proliferation (Ilic et al., 2017). These findings support the rationale to target KGDHC for cancer treatment. CPI-613 is a lipoate analog that can simultaneously inhibit both PDH and KGDHC, as lipoate is a co-factor for both enzyme complexes. While CPI-613 stimulates PDK to phosphorylate and inactivate PDH (Zachar et al., 2011), CPI-613 can also induce a burst of mitochondria ROS through acting on DLD (the E3 component of KGDHC) and suppression of the E2 subunit of KGDHC, DLST (Stuart et al., 2014). Currently, CPI-613 is being tested in phase I and II clinical trials, as a single agent or in combination with standard chemotherapy, to treat cancers (NCT02168140, NCT01902381, NCT02232152, and NCT01766219). Limited data published from these trials have already shown that CPI-613 is generally well tolerated with minimal toxicity (Pardee et al., 2014; Lycan et al., 2016). While a phase I trial indicated that CPI-613 may be effective as a single agent for treating hematological malignancies, a phase II trial for small cell lung carcinoma show no efficacy as a single agent (Pardee et al., 2014; Lycan et al., 2016).

Finally, mutations in TCA cycle gene IDH2 provide a unique opportunity for therapeutic intervention. Not only can mutant IDH serve as a biomarker, but also their neomorphic enzymatic activity can be targeted through small molecule inhibition. Currently, there are several small molecule inhibitors of mutant IDH2 in clinical development, including enasidenib (AG-221) that inhibits mutant IDH2 and AG-881 that targets both mutant IDH1 and IDH2 (Dang, 2016 #135). These compounds act by binding to the active catalytic site of mIDH1/2 enzymes and blocking the conformational change required to convert α-KG into 2-HG. AG-221 is an orally available inhibitor of mutant IDH2-R140 and IDH2-R172 (Yen et al., 2017), and is currently undergoing phase I/II clinical trials as a single agent for the treatment of AML and solid tumors (e.g., glioma and angioimmunoblastic T-cell lymphoma; NCT01915498 and NCT02273739, respectively). Preclinical data demonstrate that AG-221 can dramatically reduce 2-HG levels. Additionally, AG-221 results in cellular differentiation of tumor cells in murine xenograft models (Yen et al., 2017). Preliminary data from the AML clinical trial demonstrate that AG-221 alone led to a 41% object response rate and a 28% complete response rate. New phase I and III clinical trials will soon start and will examine the effectiveness of AG-221 alone in comparison to conventional therapy, as well as AG-221 in combination with standard induction and consolidation therapy (NCT02577406 and NCT02632708). The dual target inhibitor of mutant IDH1 and mutant IDH2, AG-881, is an orally available inhibitor that can pass the blood-brain barrier and may serve as a better option for glioma patients (Medeiros et al., 2017). Currently, AG-881 is in phase I clinical trial for AML patients with mutant IDH1/2, and a clinical trial for patients with glioma will begin soon (NCT02492737 and NCT02481154).

Future perspectives

The TCA cycle is a critical metabolic pathway that allows mammalian cells to utilize glucose, amino acids, and fatty acids. The entry of these fuels into the cycle is carefully regulated to efficiently fulfill the cell’s bioenergetic, biosynthetic, and redox balance requirements. Multiple types of cancer are marked by drastic changes to TCA cycle enzymes, which result in characteristic metabolic and epigenetic changes that are correlated with disease transformation and progression. As a result, several components of the TCA cycle may be exploited therapeutically for the treatment of disease. However, due to the importance of the TCA cycle in normal cell development, high toxicity is a concern of this approach. Interestingly, although decreased KGDHC activity is associated with neurodegenerative diseases (Gibson et al., 2010), inhibiting KGDHC through CPI-613 is well tolerated in clinical testing (Pardee et al., 2014; Lycan et al., 2016). Additionally, 50% reduction of DLST, the E2 component of KGDHC, in zebrafish significantly delays MYC-driven leukemogenesis, without causing any detectable abnormalities (Anderson et al., 2016). Importantly, others show that cancer cells with IDH mutations become insensitive to treatment with mutant IDH inhibitors in vivo, owing to the metabolic rewiring and enhanced usage of the TCA cycle (Grassian et al., 2014; Tateishi et al., 2015). Emerging studies demonstrate that cancer cells utilize the TCA cycle differently from those of normal cells, making it likely that cancer cells will be more sensitive to inhibitors targeting the reprogrammed metabolic pathways in the TCA cycle (Kishton et al., 2016). These observations support the notion that targeting the TCA cycle by small molecule inhibitors of cycle enzymes and/or enzymes regulating the cycle could serve as a productive approach for cancer treatment.

Cancer cells often escape treatment through compensatory pathways (Obre and Rossignol, 2015; Zugazagoitia et al., 2016), and the metabolic properties of cancer cells are often context-dependent (Yuneva et al., 2012; Kishton et al., 2016; Martinez-Outschoorn et al., 2017). Hence, the key for successful metabolism-based therapies against cancer relies on both the identification of the “oncometabolic” enzyme(s) responsible for metabolic reprogramming and an in-depth understanding of the activity and flexibility of the altered pathways in the context of each specific cancer type. Despite the established role of the TCA cycle in tumorigenesis, its involvement in cancer metabolism remains incompletely understood. Additionally, how the TCA cycle interacts with other biochemical and cell signaling pathways is yet to be characterized. Owing to the impact of microenvironment on cellular metabolism and oncogenic signaling, it is critically important to study the contribution of the TCA cycle to cancer metabolism and tumorigenesis in vivo. Importantly, researchers started to successfully apply untargeted/targeted metabolomics and respiratory analyses to animal model organisms. The intensive research effort in the coming years will undoubtedly deepen our understanding of the role of this central metabolic hub that was once overlooked in tumorigenesis, reveal vulnerabilities for therapeutic intervention, and eventually bring this targeted approach from infancy up to maturity.

Notes

ACKNOWLEDGEMENTS

This work was supported by a young investigator award from the Leukemia Research Foundation, a Ralph Edwards Career Development Professorship from Boston University, a Scholar grant from the St. Baldrick’s Foundation, an ignition award from Boston University, a clinical translational institute pilot from the National Institute of Health (1UL1TR001430), an institutional grant (IRG–72-001-36-IRG) from the American Cancer Society, and a grant from the Mary Kay Ash Foundation to H.F., a young investigator award from the Alex Lemonade Stand to N.M.A., P.M. acknowledges training support through T32GM008541 from the National Institutes of Health. The content of this research is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Health.

ABBREVIATIONS

α-KG, α-ketoglutarate; ACC, acetyl-CoA carboxylase; ACLY, adenosine triphosphate citrate lyase; AH, aconitate hydratase; DLD, dihydrolipoamide dehydrogenase; DLST, dihydrolipoamide S-succinyltransferase; ETC, electron transport chain; FAS, fatty acid synthase; FH, fumarase; GLS, glutaminase; GLUD, glutamate dehydrogenase; GLUT, glucose transporters; HIFs, hypoxia-inducible factors; HK, hexokinase; HLRCC, hereditary leiomyomatosis and renal cell cancer; IDH, isocitrate dehydrogenase; KGDHC, α-ketoglutarate dehydrogenase complex; LDHA, lactate dehydrogenase A; MCUL, multiple cutaneous and uterine leiomyomas; OGDH, α-KG dehydrogenase; PDH, pyruvate dehydrogenase; PDK-1, pyruvate dehydrogenase kinase 1; PFK1, phosphofructokinase 1; PHD, prolyl hydroxylases; PK, pyruvate kinase; SDH, succinate dehydrogenase; TCA, tricarboxylic acid; TET, ten-eleven translocation; VHL, von Hippel-Lindau

COMPLIANCE WITH ETHICS GUIDELINES

The authors declare no conflicts of interest. This article does not contain any studies with human or animal subjects performed by the any of the authors.

References

  1. Abbas S, Lugthart S, Kavelaars FG, Schelen A, Koenders JE, Zeilemaker A, van Putten WJ, Rijneveld AW, Lowenberg B, Valk PJ (2010) Acquired mutations in the genes encoding IDH1 and IDH2 both are recurrent aberrations in acute myeloid leukemia: prevalence and prognostic value. Blood 116:2122–2126PubMedCrossRefGoogle Scholar
  2. Adhikary S, Eilers M (2005) Transcriptional regulation and transformation by Myc proteins. Nat Rev Mol Cell Biol 6:635–645PubMedCrossRefGoogle Scholar
  3. Ahluwalia GS, Grem JL, Hao Z, Cooney DA (1990) Metabolism and action of amino acid analog anti-cancer agents. Pharmacol Ther 46:243–271PubMedCrossRefGoogle Scholar
  4. Akram M (2014) Citric acid cycle and role of its intermediates in metabolism. Cell Biochem Biophys 68:475–478PubMedCrossRefGoogle Scholar
  5. Allen EL, Ulanet DB, Pirman D, Mahoney CE, Coco J, Si Y, Chen Y, Huang L, Ren J, Choe S et al (2016) Differential aspartate usage identifies a subset of cancer cells particularly dependent on OGDH. Cell Rep 17:876–890PubMedCrossRefGoogle Scholar
  6. Amary MF, Bacsi K, Maggiani F, Damato S, Halai D, Berisha F, Pollock R, O’Donnell P, Grigoriadis A, Diss T et al (2011) IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours. J Pathol 224:334–343PubMedCrossRefGoogle Scholar
  7. Anderson NM, Li D, Peng HL, Laroche FJ, Mansour MR, Gjini E, Aioub M, Helman DJ, Roderick JE, Cheng T et al (2016) The TCA cycle transferase DLST is important for MYC-mediated leukemogenesis. Leukemia 30:1365–1374PubMedPubMedCentralCrossRefGoogle Scholar
  8. Arenas Valencia C, Rodriguez Lopez ML, Cardona Barreto AY, Garavito Rodriguez E, Arteaga Diaz CE (2017) Hereditary leiomyomatosis and renal cell cancer syndrome: identification and clinical characterization of a novel mutation in the FH gene in a Colombian family. Fam Cancer 16:117–122PubMedCrossRefGoogle Scholar
  9. Aspuria PJ, Lunt SY, Varemo L, Vergnes L, Gozo M, Beach JA, Salumbides B, Reue K, Wiedemeyer WR, Nielsen J et al (2014) Succinate dehydrogenase inhibition leads to epithelial-mesenchymal transition and reprogrammed carbon metabolism. Cancer Metab 2:21PubMedPubMedCentralCrossRefGoogle Scholar
  10. Astuti D, Latif F, Dallol A, Dahia PL, Douglas F, George E, Skoldberg F, Husebye ES, Eng C, Maher ER (2001) Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Am J Hum Genet 69:49–54PubMedPubMedCentralCrossRefGoogle Scholar
  11. Bardella C, Pollard PJ, Tomlinson I (2011) SDH mutations in cancer. Biochim Biophys Acta 1807:1432–1443PubMedCrossRefGoogle Scholar
  12. Baron-Delage S, Mahraoui L, Cadoret A, Veissiere D, Taillemite JL, Chastre E, Gespach C, Zweibaum A, Capeau J, Brot-Laroche E et al (1996) Deregulation of hexose transporter expression in Caco-2 cells by ras and polyoma middle T oncogenes. Am J Physiol 270:G314–G323PubMedGoogle Scholar
  13. Bayley JP, Kunst HP, Cascon A, Sampietro ML, Gaal J, Korpershoek E, Hinojar-Gutierrez A, Timmers HJ, Hoefsloot LH, Hermsen MA et al (2010) SDHAF2 mutations in familial and sporadic paraganglioma and phaeochromocytoma. Lancet Oncol 11:366–372PubMedCrossRefGoogle Scholar
  14. Baysal BE (2007) A recurrent stop-codon mutation in succinate dehydrogenase subunit B gene in normal peripheral blood and childhood T-cell acute leukemia. PLoS ONE 2:e436PubMedPubMedCentralCrossRefGoogle Scholar
  15. Baysal BE, Ferrell RE, Willett-Brozick JE, Lawrence EC, Myssiorek D, Bosch A, van der Mey A, Taschner PE, Rubinstein WS, Myers EN et al (2000) Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science 287:848–851PubMedCrossRefGoogle Scholar
  16. Baysal BE, Willett-Brozick JE, Lawrence EC, Drovdlic CM, Savul SA, McLeod DR, Yee HA, Brackmann DE, Slattery WH 3rd, Myers EN et al (2002) Prevalence of SDHB, SDHC, and SDHD germline mutations in clinic patients with head and neck paragangliomas. J Med Genet 39:178–183PubMedPubMedCentralCrossRefGoogle Scholar
  17. Belinsky MG, Rink L, Flieder DB, Jahromi MS, Schiffman JD, Godwin AK, Mehren M (2013a) Overexpression of insulin-like growth factor 1 receptor and frequent mutational inactivation of SDHA in wild-type SDHB-negative gastrointestinal stromal tumors. Genes Chromosomes Cancer 52:214–224PubMedCrossRefGoogle Scholar
  18. Belinsky MG, Rink L, von Mehren M (2013b) Succinate dehydrogenase deficiency in pediatric and adult gastrointestinal stromal tumors. Front Oncol 3:117PubMedPubMedCentralCrossRefGoogle Scholar
  19. Bennedbaek M, Rossing M, Rasmussen AK, Gerdes AM, Skytte AB, Jensen UB, Nielsen FC, Hansen TV (2016) Identification of eight novel SDHB, SDHC, SDHD germline variants in Danish pheochromocytoma/paraganglioma patients. Hered Cancer Clin Pract 14:13PubMedPubMedCentralCrossRefGoogle Scholar
  20. Bensaad K, Tsuruta A, Selak MA, Vidal MN, Nakano K, Bartrons R, Gottlieb E, Vousden KH (2006) TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell 126:107–120PubMedCrossRefGoogle Scholar
  21. Bensaad K, Cheung EC, Vousden KH (2009) Modulation of intracellular ROS levels by TIGAR controls autophagy. EMBO J 28:3015–3026PubMedPubMedCentralCrossRefGoogle Scholar
  22. Berg JM, Tymoczko JL, Stryer L (2002) Biochemistry, 5th edn. W. H. Freeman and Company, New YorkGoogle Scholar
  23. Birnbaum MJ, Haspel HC, Rosen OM (1987) Transformation of rat fibroblasts by FSV rapidly increases glucose transporter gene transcription. Science (New York, NY) 235:1495–1498CrossRefGoogle Scholar
  24. Bolzoni M, Chiu M, Accardi F, Vescovini R, Airoldi I, Storti P, Todoerti K, Agnelli L, Missale G, Andreoli R et al (2016) Dependence on glutamine uptake and glutamine addiction characterize myeloma cells: a new attractive target. Blood 128:667–679PubMedCrossRefGoogle Scholar
  25. Brosnan JT (2003) Interorgan amino acid transport and its regulation. J Nutr 133:2068S–2072SPubMedCrossRefGoogle Scholar
  26. Burnichon N, Briere JJ, Libe R, Vescovo L, Riviere J, Tissier F, Jouanno E, Jeunemaitre X, Benit P, Tzagoloff A et al (2010) SDHA is a tumor suppressor gene causing paraganglioma. Hum Mol Genet 19:3011–3020PubMedPubMedCentralCrossRefGoogle Scholar
  27. Cairns RA, Iqbal J, Lemonnier F, Kucuk C, de Leval L, Jais JP, Parrens M, Martin A, Xerri L, Brousset P et al (2012) IDH2 mutations are frequent in angioimmunoblastic T-cell lymphoma. Blood 119:1901–1903PubMedPubMedCentralCrossRefGoogle Scholar
  28. Carvajal-Carmona LG, Alam NA, Pollard PJ, Jones AM, Barclay E, Wortham N, Pignatelli M, Freeman A, Pomplun S, Ellis I et al (2006) Adult leydig cell tumors of the testis caused by germline fumarate hydratase mutations. J Clin Endocrinol Metab 91:3071–3075PubMedCrossRefGoogle Scholar
  29. Chan WK, Lorenzi PL, Anishkin A, Purwaha P, Rogers DM, Sukharev S, Rempe SB, Weinstein JN (2014) The glutaminase activity of L-asparaginase is not required for anticancer activity against ASNS-negative cells. Blood 123:3596–3606PubMedPubMedCentralCrossRefGoogle Scholar
  30. Chandel NS (2015) Navigating metabolism. Cold Spring Harbor Laboratory Press, Cold Spring HarborGoogle Scholar
  31. Chen JQ, Russo J (2012) Dysregulation of glucose transport, glycolysis, TCA cycle and glutaminolysis by oncogenes and tumor suppressors in cancer cells. Biochim Biophys Acta 1826:370–384PubMedGoogle Scholar
  32. Chen L, Liu T, Zhou J, Wang Y, Wang X, Di W, Zhang S (2014) Citrate synthase expression affects tumor phenotype and drug resistance in human ovarian carcinoma. PLoS ONE 9:e115708PubMedPubMedCentralCrossRefGoogle Scholar
  33. Cheng T, Sudderth J, Yang C, Mullen AR, Jin ES, Mates JM, DeBerardinis RJ (2011) Pyruvate carboxylase is required for glutamine-independent growth of tumor cells. Proc Natl Acad Sci USA 108:8674–8679PubMedPubMedCentralCrossRefGoogle Scholar
  34. Chowdhury R, Yeoh KK, Tian YM, Hillringhaus L, Bagg EA, Rose NR, Leung IK, Li XS, Woon EC, Yang M et al (2011) The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases. EMBO Rep 12:463–469PubMedPubMedCentralCrossRefGoogle Scholar
  35. Clarke SD (1993) Regulation of fatty acid synthase gene expression: an approach for reducing fat accumulation. J Anim Sci 71:1957–1965PubMedCrossRefGoogle Scholar
  36. Contractor T, Harris CR (2012) p53 negatively regulates transcription of the pyruvate dehydrogenase kinase Pdk2. Cancer Res 72:560–567PubMedCrossRefGoogle Scholar
  37. Cummins TD, Holden CR, Sansbury BE, Gibb AA, Shah J, Zafar N, Tang Y, Hellmann J, Rai SN, Spite M et al (2014) Metabolic remodeling of white adipose tissue in obesity. Am J Physiol Endocrinol Metab 307:E262–E277PubMedPubMedCentralCrossRefGoogle Scholar
  38. Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM, Fantin VR, Jang HG, Jin S, Keenan MC et al (2009) Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462:739–744PubMedPubMedCentralCrossRefGoogle Scholar
  39. Dannenberg H, Dinjens WN, Abbou M, Van Urk H, Pauw BK, Mouwen D, Mooi WJ, de Krijger RR (2002) Frequent germ-line succinate dehydrogenase subunit D gene mutations in patients with apparently sporadic parasympathetic paraganglioma. Clin Cancer Res 8:2061–2066PubMedGoogle Scholar
  40. DeBerardinis RJ, Cheng T (2010) Q’s next: the diverse functions of glutamine in metabolism, cell biology and cancer. Oncogene 29:313PubMedCrossRefGoogle Scholar
  41. DeBerardinis RJ, Mancuso A, Daikhin E, Nissim I, Yudkoff M, Wehrli S, Thompson CB (2007) Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc Natl Acad Sci USA 104:19345PubMedPubMedCentralCrossRefGoogle Scholar
  42. Douwes Dekker PB, Hogendoorn PC, Kuipers-Dijkshoorn N, Prins FA, van Duinen SG, Taschner PE, van der Mey AG, Cornelisse CJ (2003) SDHD mutations in head and neck paragangliomas result in destabilization of complex II in the mitochondrial respiratory chain with loss of enzymatic activity and abnormal mitochondrial morphology. J Pathol 201:480–486PubMedCrossRefGoogle Scholar
  43. Dwight T, Mann K, Benn DE, Robinson BG, McKelvie P, Gill AJ, Winship I, Clifton-Bligh RJ (2013) Familial SDHA mutation associated with pituitary adenoma and pheochromocytoma/paraganglioma. J Clin Endocrinol Metab 98:E1103–E1108PubMedCrossRefGoogle Scholar
  44. Eagle H (1955) The minimum vitamin requirements of the L and HeLa cells in tissue culture, the production of specific vitamin deficiencies, and their cure. J Exp Med 102:595–600PubMedPubMedCentralCrossRefGoogle Scholar
  45. Edmunds LR, Sharma L, Kang A, Lu J, Vockley J, Basu S, Uppala R, Goetzman ES, Beck ME, Scott D et al (2015) c-Myc programs fatty acid metabolism and dictates acetyl-CoA abundance and fate. J Biol Chem 290:20100PubMedPubMedCentralCrossRefGoogle Scholar
  46. Eng C, Kiuru M, Fernandez MJ, Aaltonen LA (2003) A role for mitochondrial enzymes in inherited neoplasia and beyond. Nat Rev Cancer 3:193–202PubMedCrossRefGoogle Scholar
  47. Evenepoel L, Papathomas TG, Krol N, Korpershoek E, de Krijger RR, Persu A, Dinjens WN (2015) Toward an improved definition of the genetic and tumor spectrum associated with SDH germ-line mutations. Genet Med 17:610–620PubMedCrossRefGoogle Scholar
  48. Fedorova MS, Kudryavtseva AV, Lakunina VA, Snezhkina AV, Volchenko NN, Slavnova EN, Danilova TV, Sadritdinova AF, Melnikova NV, Belova AA et al (2015) Downregulation of OGDHL expression is associated with promoter hypermethylation in colorectal cancer. Mol Biol (Mosk) 49:678–688CrossRefGoogle Scholar
  49. Gabay M, Li Y, Felsher DW (2014) MYC activation is a hallmark of cancer initiation and maintenance. Cold Spring Harb Perspect Med. doi: 10.1101/cshperspect.a014241 PubMedPubMedCentralGoogle Scholar
  50. Galera-Ruiz H, Gonzalez-Campora R, Rey-Barrera M, Rollon-Mayordomo A, Garcia-Escudero A, Fernandez-Santos JM, DeMiguel M, Galera-Davidson H (2008) W43X SDHD mutation in sporadic head and neck paraganglioma. Anal Quant Cytol Histol 30:119–123PubMedGoogle Scholar
  51. Gameiro PA, Yang J, Metelo AM, Perez-Carro R, Baker R, Wang Z, Arreola A, Rathmell WK, Olumi A, Lopez-Larrubia P et al (2013) In vivo HIF-mediated reductive carboxylation is regulated by citrate levels and sensitizes VHL-deficient cells to glutamine deprivation. Cell Metab 17:372–385PubMedPubMedCentralCrossRefGoogle Scholar
  52. Gao P, Tchernyshyov I, Chang TC, Lee YS, Kita K, Ochi T, Zeller KI, De Marzo AM, Van Eyk JE, Mendell JT et al (2009) c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature 458:762–765PubMedPubMedCentralCrossRefGoogle Scholar
  53. Gao C, Shen Y, Jin F, Miao Y, Qiu X (2016) Cancer stem cells in small cell lung cancer cell line H446: higher dependency on oxidative phosphorylation and mitochondrial substrate-level phosphorylation than non-stem cancer cells. PLoS ONE 11:e0154576PubMedPubMedCentralCrossRefGoogle Scholar
  54. Gardie B, Remenieras A, Kattygnarath D, Bombled J, Lefevre S, Perrier-Trudova V, Rustin P, Barrois M, Slama A, Avril MF et al (2011) Novel FH mutations in families with hereditary leiomyomatosis and renal cell cancer (HLRCC) and patients with isolated type 2 papillary renal cell carcinoma. J Med Genet 48:226–234PubMedCrossRefGoogle Scholar
  55. Gatenby RA, Gillies RJ (2004) Why do cancers have high aerobic glycolysis? Nat Rev Cancer 4:891–899PubMedCrossRefGoogle Scholar
  56. Ghiam AF, Cairns RA, Thoms J, Dal Pra A, Ahmed O, Meng A, Mak TW, Bristow RG (2012) IDH mutation status in prostate cancer. Oncogene 31:3826PubMedCrossRefGoogle Scholar
  57. Gibson GE, Starkov A, Blass JP, Ratan RR, Beal MF (2010) Cause and consequence: mitochondrial dysfunction initiates and propagates neuronal dysfunction, neuronal death and behavioral abnormalities in age-associated neurodegenerative diseases. Biochim Biophys Acta 1802:122–134PubMedCrossRefGoogle Scholar
  58. Gillies RJ, Gatenby RA (2007) Adaptive landscapes and emergent phenotypes: why do cancers have high glycolysis? J Bioenerg Biomembr 39:251–257PubMedCrossRefGoogle Scholar
  59. Gimm O, Armanios M, Dziema H, Neumann HP, Eng C (2000) Somatic and occult germ-line mutations in SDHD, a mitochondrial complex II gene, in nonfamilial pheochromocytoma. Cancer Res 60:6822–6825PubMedGoogle Scholar
  60. Gordan JD, Simon MC (2007) Hypoxia-inducible factors: central regulators of the tumor phenotype. Curr Opin Genet Dev 17:71–77PubMedPubMedCentralCrossRefGoogle Scholar
  61. Gottlieb E, Tomlinson IP (2005) Mitochondrial tumour suppressors: a genetic and biochemical update. Nat Rev Cancer 5:857–866PubMedCrossRefGoogle Scholar
  62. Grassian AR, Parker SJ, Davidson SM, Divakaruni AS, Green CR, Zhang X, Slocum KL, Pu M, Lin F, Vickers C et al (2014) IDH1 mutations alter citric acid cycle metabolism and increase dependence on oxidative mitochondrial metabolism. Cancer Res 74:3317–3331PubMedPubMedCentralCrossRefGoogle Scholar
  63. Griffiths M, Keast D, Patrick G, Crawford M, Palmer TN (1993) The role of glutamine and glucose analogues in metabolic inhibition of human myeloid leukaemia in vitro. Int J Biochem 25:1749–1755PubMedCrossRefGoogle Scholar
  64. Gross S, Cairns RA, Minden MD, Driggers EM, Bittinger MA, Jang HG, Sasaki M, Jin S, Schenkein DP, Su SM et al (2010) Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations. J Exp Med 207:339–344PubMedPubMedCentralCrossRefGoogle Scholar
  65. Guo JY, Chen HY, Mathew R, Fan J, Strohecker AM, Karsli-Uzunbas G, Kamphorst JJ, Chen G, Lemons JM, Karantza V et al (2011) Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis. Genes Dev 25:460–470PubMedPubMedCentralCrossRefGoogle Scholar
  66. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674PubMedCrossRefGoogle Scholar
  67. Hao HX, Khalimonchuk O, Schraders M, Dephoure N, Bayley JP, Kunst H, Devilee P, Cremers CW, Schiffman JD, Bentz BG et al (2009) SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma. Science 325:1139–1142PubMedCrossRefGoogle Scholar
  68. Hemerly JP, Bastos AU, Cerutti JM (2010) Identification of several novel non-p.R132 IDH1 variants in thyroid carcinomas. Eur J Endocrinol 163:747–755PubMedCrossRefGoogle Scholar
  69. Hoekstra AS, de Graaff MA, Briaire-de Bruijn IH, Ras C, Seifar RM, van Minderhout I, Cornelisse CJ, Hogendoorn PC, Breuning MH, Suijker J et al (2015) Inactivation of SDH and FH cause loss of 5hmC and increased H3K9me3 in paraganglioma/pheochromocytoma and smooth muscle tumors. Oncotarget 6:38777–38788PubMedPubMedCentralGoogle Scholar
  70. Hoque MO, Kim MS, Ostrow KL, Liu J, Wisman GB, Park HL, Poeta ML, Jeronimo C, Henrique R, Lendvai A et al (2008) Genome-wide promoter analysis uncovers portions of the cancer methylome. Cancer Res 68:2661–2670PubMedPubMedCentralCrossRefGoogle Scholar
  71. Houten SM, Wanders RJ (2010) A general introduction to the biochemistry of mitochondrial fatty acid beta-oxidation. J Inherit Metab Dis 33:469–477PubMedPubMedCentralCrossRefGoogle Scholar
  72. Ilic N, Birsoy K, Aguirre AJ, Kory N, Pacold ME, Singh S, Moody SE, DeAngelo JD, Spardy NA, Freinkman E et al (2017) PIK3CA mutant tumors depend on oxoglutarate dehydrogenase. Proc Natl Acad Sci USA 114:E3434–E3443PubMedPubMedCentralCrossRefGoogle Scholar
  73. Italiano A, Chen CL, Sung YS, Singer S, DeMatteo RP, LaQuaglia MP, Besmer P, Socci N, Antonescu CR (2012) SDHA loss of function mutations in a subset of young adult wild-type gastrointestinal stromal tumors. BMC Cancer 12:408PubMedPubMedCentralCrossRefGoogle Scholar
  74. Jacque N, Ronchetti AM, Larrue C, Meunier G, Birsen R, Willems L, Saland E, Decroocq J, Maciel TT, Lambert M et al (2015) Targeting glutaminolysis has antileukemic activity in acute myeloid leukemia and synergizes with BCL-2 inhibition. Blood 126:1346–1356PubMedPubMedCentralCrossRefGoogle Scholar
  75. Janeway KA, Kim SY, Lodish M, Nose V, Rustin P, Gaal J, Dahia PL, Liegl B, Ball ER, Raygada M et al (2011) Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations. Proc Natl Acad Sci USA 108:314–318PubMedCrossRefGoogle Scholar
  76. Jiang Q, Zhang Y, Zhou YH, Hou YY, Wang JY, Li JL, Li M, Tong HX, Lu WQ (2015) A novel germline mutation in SDHA identified in a rare case of gastrointestinal stromal tumor complicated with renal cell carcinoma. Int J Clin Exp Pathol 8:12188–12197PubMedPubMedCentralGoogle Scholar
  77. Juang HH (2004) Modulation of mitochondrial aconitase on the bioenergy of human prostate carcinoma cells. Mol Genet Metab 81:244–252PubMedCrossRefGoogle Scholar
  78. Kamphorst JJ, Nofal M, Commisso C, Hackett SR, Lu W, Grabocka E, Vander Heiden MG, Miller G, Drebin JA, Bar-Sagi D et al (2015) Human pancreatic cancer tumors are nutrient poor and tumor cells actively scavenge extracellular protein. Cancer Res 75:544–553PubMedPubMedCentralCrossRefGoogle Scholar
  79. Kang MR, Kim MS, Oh JE, Kim YR, Song SY, Seo SI, Lee JY, Yoo NJ, Lee SH (2009) Mutational analysis of IDH1 codon 132 in glioblastomas and other common cancers. Int J Cancer 125:353–355PubMedCrossRefGoogle Scholar
  80. Kerr EM, Gaude E, Turrell FK, Frezza C, Martins CP (2016) Mutant Kras copy number defines metabolic reprogramming and therapeutic susceptibilities. Nature 531(7592):110–113PubMedPubMedCentralCrossRefGoogle Scholar
  81. Kim JW, Tchernyshyov I, Semenza GL, Dang CV (2006) HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab 3:177–185PubMedCrossRefGoogle Scholar
  82. Kishton RJ, Rathmell JC (2015) Novel therapeutic targets of tumor metabolism. Cancer J 21:62–69PubMedPubMedCentralCrossRefGoogle Scholar
  83. Kishton RJ, Barnes CE, Nichols AG, Cohen S, Gerriets VA, Siska PJ, Macintyre AN, Goraksha-Hicks P, de Cubas AA, Liu T et al (2016) AMPK is essential to balance glycolysis and mitochondrial metabolism to control T-ALL cell stress and survival. Cell Metab 23:649–662PubMedPubMedCentralCrossRefGoogle Scholar
  84. Koivunen P, Lee S, Duncan CG, Lopez G, Lu G, Ramkissoon S, Losman JA, Joensuu P, Bergmann U, Gross S et al (2012) Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation. Nature 483:484–488PubMedPubMedCentralCrossRefGoogle Scholar
  85. Kondoh H, Lleonart ME, Gil J, Wang J, Degan P, Peters G, Martinez D, Carnero A, Beach D (2005) Glycolytic enzymes can modulate cellular life span. Cancer Res 65:177–185PubMedGoogle Scholar
  86. Korpershoek E, Favier J, Gaal J, Burnichon N, van Gessel B, Oudijk L, Badoual C, Gadessaud N, Venisse A, Bayley JP et al (2011) SDHA immunohistochemistry detects germline SDHA gene mutations in apparently sporadic paragangliomas and pheochromocytomas. J Clin Endocrinol Metab 96:E1472–E1476PubMedCrossRefGoogle Scholar
  87. Kosmider O, Gelsi-Boyer V, Slama L, Dreyfus F, Beyne-Rauzy O, Quesnel B, Hunault-Berger M, Slama B, Vey N, Lacombe C et al (2010) Mutations of IDH1 and IDH2 genes in early and accelerated phases of myelodysplastic syndromes and MDS/myeloproliferative neoplasms. Leukemia 24:1094–1096PubMedCrossRefGoogle Scholar
  88. Kruiswijk F, Labuschagne CF, Vousden KH (2015) p53 in survival, death and metabolic health: a lifeguard with a licence to kill. Nat Rev Mol Cell Biol 16:393–405PubMedCrossRefGoogle Scholar
  89. Launonen V, Vierimaa O, Kiuru M, Isola J, Roth S, Pukkala E, Sistonen P, Herva R, Aaltonen LA (2001) Inherited susceptibility to uterine leiomyomas and renal cell cancer. Proc Natl Acad Sci U S A 98:3387–3392PubMedPubMedCentralCrossRefGoogle Scholar
  90. Le A, Lane AN, Hamaker M, Bose S, Gouw A, Barbi J, Tsukamoto T, Rojas CJ, Slusher BS, Zhang H et al (2012) Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells. Cell Metab 15:110–121PubMedPubMedCentralCrossRefGoogle Scholar
  91. Lee SC, Chionh SB, Chong SM, Taschner PE (2003) Hereditary paraganglioma due to the SDHD M1I mutation in a second Chinese family: a founder effect? Laryngoscope 113:1055–1058PubMedCrossRefGoogle Scholar
  92. Lemonnier F, Cairns RA, Inoue S, Li WY, Dupuy A, Broutin S, Martin N, Fataccioli V, Pelletier R, Wakeham A et al (2016) The IDH2 R172K mutation associated with angioimmunoblastic T-cell lymphoma produces 2HG in T cells and impacts lymphoid development. Proc Natl Acad Sci U S A 113:15084–15089PubMedPubMedCentralCrossRefGoogle Scholar
  93. Lin CC, Cheng TL, Tsai WH, Tsai HJ, Hu KH, Chang HC, Yeh CW, Chen YC, Liao CC, Chang WT (2012) Loss of the respiratory enzyme citrate synthase directly links the Warburg effect to tumor malignancy. Sci Rep 2:785PubMedPubMedCentralCrossRefGoogle Scholar
  94. Lo M, Wang YZ, Gout PW (2008) The x(c)- cystine/glutamate antiporter: a potential target for therapy of cancer and other diseases. J Cell Physiol 215:593–602PubMedCrossRefGoogle Scholar
  95. Lycan TW, Pardee TS, Petty WJ, Bonomi M, Alistar A, Lamar ZS, Isom S, Chan MD, Miller AA, Ruiz J (2016) A phase II clinical trial of CPI-613 in patients with relapsed or refractory small cell lung carcinoma. PLoS ONE 11:e0164244PubMedPubMedCentralCrossRefGoogle Scholar
  96. Mannelli M, Ercolino T, Giache V, Simi L, Cirami C, Parenti G (2007) Genetic screening for pheochromocytoma: should SDHC gene analysis be included? J Med Genet 44:586–587PubMedPubMedCentralCrossRefGoogle Scholar
  97. Mardis ER, Ding L, Dooling DJ, Larson DE, McLellan MD, Chen K, Koboldt DC, Fulton RS, Delehaunty KD, McGrath SD et al (2009) Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med 361:1058–1066PubMedPubMedCentralCrossRefGoogle Scholar
  98. Márquez J, Alonso FJ, Matés JM, Segura JA, Martín-Rufián M, Campos-Sandoval JA (2017) Glutamine addiction in gliomas. Neurochem Res 42(6):1735–1746PubMedCrossRefGoogle Scholar
  99. Martinez-Outschoorn UE, Peiris-Pages M, Pestell RG, Sotgia F, Lisanti MP (2017) Cancer metabolism: a therapeutic perspective. Nat Rev Clin Oncol 14:11–31PubMedCrossRefGoogle Scholar
  100. Mayers JR, Wu C, Clish CB, Kraft P, Torrence ME, Fiske BP, Yuan C, Bao Y, Townsend MK, Tworoger SS et al (2014) Elevation of circulating branched-chain amino acids is an early event in human pancreatic adenocarcinoma development. Nat Med 20:1193–1198PubMedPubMedCentralCrossRefGoogle Scholar
  101. McWhinney SR, Pasini B, Stratakis CA (2007) Familial gastrointestinal stromal tumors and germ-line mutations. N Engl J Med 357:1054–1056PubMedCrossRefGoogle Scholar
  102. Medeiros BC, Fathi AT, DiNardo CD, Pollyea DA, Chan SM, Swords R (2017) Isocitrate dehydrogenase mutations in myeloid malignancies. Leukemia 31:272–281PubMedCrossRefGoogle Scholar
  103. Menendez JA, Ropero S, Mehmi I, Atlas E, Colomer R, Lupu R (2004) Overexpression and hyperactivity of breast cancer-associated fatty acid synthase (oncogenic antigen-519) is insensitive to normal arachidonic fatty acid-induced suppression in lipogenic tissues but it is selectively inhibited by tumoricidal alpha-linolenic and gamma-linolenic fatty acids: a novel mechanism by which dietary fat can alter mammary tumorigenesis. Int J Oncol 24:1369–1383PubMedGoogle Scholar
  104. Metallo CM, Gameiro PA, Bell EL, Mattaini KR, Yang J, Hiller K, Jewell CM, Johnson ZR, Irvine DJ, Guarente L et al (2011) Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature 481:380–384PubMedPubMedCentralCrossRefGoogle Scholar
  105. Meyer N, Penn LZ (2008) Reflecting on 25 years with MYC. Nat Rev Cancer 8:976–990PubMedCrossRefGoogle Scholar
  106. Miettinen M, Lasota J (2014) Succinate dehydrogenase deficient gastrointestinal stromal tumors (GISTs)—a review. Int J Biochem Cell Biol 53:514–519PubMedCrossRefGoogle Scholar
  107. Miettinen M, Killian JK, Wang ZF, Lasota J, Lau C, Jones L, Walker R, Pineda M, Zhu YJ, Kim SY et al (2013) Immunohistochemical loss of succinate dehydrogenase subunit A (SDHA) in gastrointestinal stromal tumors (GISTs) signals SDHA germline mutation. Am J Surg Pathol 37:234–240PubMedPubMedCentralCrossRefGoogle Scholar
  108. Migita T, Narita T, Nomura K, Miyagi E, Inazuka F, Matsuura M, Ushijima M, Mashima T, Seimiya H, Satoh Y et al (2008) ATP citrate lyase: activation and therapeutic implications in non-small cell lung cancer. Cancer Res 68:8547–8554PubMedCrossRefGoogle Scholar
  109. Mullen AR, Wheaton WW, Jin ES, Chen PH, Sullivan LB, Cheng T, Yang Y, Linehan WM, Chandel NS, DeBerardinis RJ (2011) Reductive carboxylation supports growth in tumour cells with defective mitochondria. Nature 481:385–388PubMedPubMedCentralCrossRefGoogle Scholar
  110. Murugan AK, Bojdani E, Xing M (2010) Identification and functional characterization of isocitrate dehydrogenase 1 (IDH1) mutations in thyroid cancer. Biochem Biophys Res Commun 393:555–559PubMedPubMedCentralCrossRefGoogle Scholar
  111. Neumann HP, Pawlu C, Peczkowska M, Bausch B, McWhinney SR, Muresan M, Buchta M, Franke G, Klisch J, Bley TA et al (2004) Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. JAMA 292:943–951PubMedCrossRefGoogle Scholar
  112. Neumann HP, Erlic Z, Boedeker CC, Rybicki LA, Robledo M, Hermsen M, Schiavi F, Falcioni M, Kwok P, Bauters C et al (2009) Clinical predictors for germline mutations in head and neck paraganglioma patients: cost reduction strategy in genetic diagnostic process as fall-out. Cancer Res 69:3650–3656PubMedCrossRefGoogle Scholar
  113. Niemann S, Muller U (2000) Mutations in SDHC cause autosomal dominant paraganglioma, type 3. Nat Genet 26:268–270PubMedCrossRefGoogle Scholar
  114. Obre E, Rossignol R (2015) Emerging concepts in bioenergetics and cancer research: metabolic flexibility, coupling, symbiosis, switch, oxidative tumors, metabolic remodeling, signaling and bioenergetic therapy. Int J Biochem Cell Biol 59:167–181PubMedCrossRefGoogle Scholar
  115. Oettgen HF, Old LJ, Boyse EA, Campbell HA, Philips FS, Clarkson BD, Tallal L, Leeper RD, Schwartz MK, Kim JH (1967) Inhibition of leukemias in man by L-asparaginase. Cancer Res 27:2619–2631PubMedGoogle Scholar
  116. Ohgaki H, Kleihues P (2013) The definition of primary and secondary glioblastoma. Clin Cancer Res 19:764–772PubMedCrossRefGoogle Scholar
  117. Ostrow KL, Park HL, Hoque MO, Kim MS, Liu J, Argani P, Westra W, Van Criekinge W, Sidransky D (2009) Pharmacologic unmasking of epigenetically silenced genes in breast cancer. Clin Cancer Res 15:1184–1191PubMedPubMedCentralCrossRefGoogle Scholar
  118. Oudijk L, Gaal J, Korpershoek E, van Nederveen FH, Kelly L, Schiavon G, Verweij J, Mathijssen RH, den Bakker MA, Oldenburg RA et al (2013) SDHA mutations in adult and pediatric wild-type gastrointestinal stromal tumors. Mod Pathol 26:456–463PubMedCrossRefGoogle Scholar
  119. Ovejera AA, Houchens DP, Catane R, Sheridan MA, Muggia FM (1979) Efficacy of 6-diazo-5-oxo-L-norleucine and N-[N-gamma-glutamyl-6-diazo-5-oxo-norleucinyl]-6-diazo-5-oxo-norleucine against experimental tumors in conventional and nude mice. Cancer Res 39:3220–3224PubMedGoogle Scholar
  120. Paik JY, Toon CW, Benn DE, High H, Hasovitz C, Pavlakis N, Clifton-Bligh RJ, Gill AJ (2014) Renal carcinoma associated with succinate dehydrogenase B mutation: a new and unique subtype of renal carcinoma. J Clin Oncol 32:e10–e13PubMedCrossRefGoogle Scholar
  121. Pantaleo MA, Astolfi A, Indio V, Moore R, Thiessen N, Heinrich MC, Gnocchi C, Santini D, Catena F, Formica S et al (2011) SDHA loss-of-function mutations in KIT-PDGFRA wild-type gastrointestinal stromal tumors identified by massively parallel sequencing. J Natl Cancer Inst 103:983–987PubMedCrossRefGoogle Scholar
  122. Papathanassiou D, Bruna-Muraille C, Jouannaud C, Gagneux-Lemoussu L, Eschard JP, Liehn JC (2009) Single-photon emission computed tomography combined with computed tomography (SPECT/CT) in bone diseases. Joint Bone Spine 76:474–480PubMedCrossRefGoogle Scholar
  123. Pardanani A, Lasho TL, Finke CM, Mai M, McClure RF, Tefferi A (2010) IDH1 and IDH2 mutation analysis in chronic- and blast-phase myeloproliferative neoplasms. Leukemia 24:1146–1151PubMedCrossRefGoogle Scholar
  124. Pardee TS, Lee K, Luddy J, Maturo C, Rodriguez R, Isom S, Miller LD, Stadelman KM, Levitan D, Hurd D et al (2014) A phase I study of the first-in-class antimitochondrial metabolism agent, CPI-613, in patients with advanced hematologic malignancies. Clin Cancer Res 20:5255–5264PubMedPubMedCentralCrossRefGoogle Scholar
  125. Parmentier JH, Maggi M, Tarasco E, Scotti C, Avramis VI, Mittelman SD (2015) Glutaminase activity determines cytotoxicity of L-asparaginases on most leukemia cell lines. Leuk Res 39:757–762PubMedPubMedCentralCrossRefGoogle Scholar
  126. Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Siu IM, Gallia GL et al (2008) An integrated genomic analysis of human glioblastoma multiforme. Science 321:1807–1812PubMedPubMedCentralCrossRefGoogle Scholar
  127. Pasini B, McWhinney SR, Bei T, Matyakhina L, Stergiopoulos S, Muchow M, Boikos SA, Ferrando B, Pacak K, Assie G et al (2008) Clinical and molecular genetics of patients with the Carney–Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD. Eur J Hum Genet 16:79–88PubMedCrossRefGoogle Scholar
  128. Pathania D, Millard M, Neamati N (2009) Opportunities in discovery and delivery of anticancer drugs targeting mitochondria and cancer cell metabolism. Adv Drug Deliv Rev 61:1250–1275PubMedCrossRefGoogle Scholar
  129. Pavlova NN, Thompson CB (2016) The emerging hallmarks of cancer metabolism. Cell Metab 23:27–47PubMedPubMedCentralCrossRefGoogle Scholar
  130. Peczkowska M, Cascon A, Prejbisz A, Kubaszek A, Cwikla BJ, Furmanek M, Erlic Z, Eng C, Januszewicz A, Neumann HP (2008) Extra-adrenal and adrenal pheochromocytomas associated with a germline SDHC mutation. Nat Clin Pract Endocrinol Metab 4:111–115PubMedCrossRefGoogle Scholar
  131. Pfaffenroth EC, Linehan WM (2008) Genetic basis for kidney cancer: opportunity for disease-specific approaches to therapy. Expert Opin Biol Ther 8:779–790PubMedPubMedCentralCrossRefGoogle Scholar
  132. Pillai S, Gopalan V, Lo CY, Liew V, Smith RA, Lam AK (2017) Silent genetic alterations identified by targeted next-generation sequencing in pheochromocytoma/paraganglioma: a clinicopathological correlations. Exp Mol Pathol 102:41–46PubMedCrossRefGoogle Scholar
  133. Pollard PJ, Briere JJ, Alam NA, Barwell J, Barclay E, Wortham NC, Hunt T, Mitchell M, Olpin S, Moat SJ et al (2005) Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations. Hum Mol Genet 14:2231–2239PubMedCrossRefGoogle Scholar
  134. Pusch S, Sahm F, Meyer J, Mittelbronn M, Hartmann C, von Deimling A (2011) Glioma IDH1 mutation patterns off the beaten track. Neuropathol Appl Neurobiol 37:428–430PubMedCrossRefGoogle Scholar
  135. Pylayeva-Gupta Y, Grabocka E, Bar-Sagi D (2011) RAS oncogenes: weaving a tumorigenic web. Nat Rev Cancer 11:761–774PubMedPubMedCentralCrossRefGoogle Scholar
  136. Reitzer LJ, Wice BM, Kennell D (1979) Evidence that glutamine, not sugar, is the major energy source for cultured HeLa cells. J Biol Chem 254:2669–2676PubMedGoogle Scholar
  137. Ricketts C, Woodward ER, Killick P, Morris MR, Astuti D, Latif F, Maher ER (2008) Germline SDHB mutations and familial renal cell carcinoma. J Natl Cancer Inst 100:1260–1262PubMedCrossRefGoogle Scholar
  138. Rodman SN, Spence JM, Ronnfeldt TJ, Zhu Y, Solst SR, O’Neill RA, Allen BG, Guan X, Spitz DR, Fath MA (2016) Enhancement of radiation response in breast cancer stem cells by inhibition of thioredoxin- and glutathione-dependent metabolism. Radiat Res 186:385–395PubMedPubMedCentralCrossRefGoogle Scholar
  139. Roh JL, Kim EH, Jang HJ, Park JY, Shin D (2016) Induction of ferroptotic cell death for overcoming cisplatin resistance of head and neck cancer. Cancer Lett 381:96–103PubMedCrossRefGoogle Scholar
  140. Rustin P, Bourgeron T, Parfait B, Chretien D, Munnich A, Rötig A (1997) Inborn errors of the Krebs cycle: a group of unusual mitochondrial diseases in human. Biochim Biophys Acta 1361:185–197PubMedCrossRefGoogle Scholar
  141. Sajnani K, Islam F, Smith RA, Gopalan V, Lam AK (2017) Genetic alterations in Krebs cycle and its impact on cancer pathogenesis. Biochimie 135:164–172PubMedCrossRefGoogle Scholar
  142. Schimke RN, Collins DL, Stolle CA (2010) Paraganglioma, neuroblastoma, and a SDHB mutation: resolution of a 30-year-old mystery. Am J Med Genet A 152A:1531–1535PubMedGoogle Scholar
  143. Schlichtholz B, Turyn J, Goyke E, Biernacki M, Jaskiewicz K, Sledzinski Z, Swierczynski J (2005) Enhanced citrate synthase activity in human pancreatic cancer. Pancreas 30:99–104PubMedCrossRefGoogle Scholar
  144. Seltzer MJ, Bennett BD, Joshi AD, Gao P, Thomas AG, Ferraris DV, Tsukamoto T, Rojas CJ, Slusher BS, Rabinowitz JD et al (2010) Inhibition of glutaminase preferentially slows growth of glioma cells with mutant IDH1. Cancer Res 70:8981–8987PubMedPubMedCentralCrossRefGoogle Scholar
  145. Semenza GL (2012) Hypoxia-inducible factors in physiology and medicine. Cell 148:399–408PubMedPubMedCentralCrossRefGoogle Scholar
  146. Shi J, Sun B, Shi W, Zuo H, Cui D, Ni L, Chen J (2015) Decreasing GSH and increasing ROS in chemosensitivity gliomas with IDH1 mutation. Tumour Biol 36:655–662PubMedCrossRefGoogle Scholar
  147. Shitara K, Doi T, Nagano O, Fukutani M, Hasegawa H, Nomura S, Sato A, Kuwata T, Asai K, Einaga Y et al (2017) Phase 1 study of sulfasalazine and cisplatin for patients with CD44v-positive gastric cancer refractory to cisplatin (EPOC1407). Gastric Cancer. doi: 10.1007/s10120-017-0720-y Google Scholar
  148. Simi L, Sestini R, Ferruzzi P, Gagliano MS, Gensini F, Mascalchi M, Guerrini L, Pratesi C, Pinzani P, Nesi G et al (2005) Phenotype variability of neural crest derived tumours in six Italian families segregating the same founder SDHD mutation Q109X. J Med Genet 42:e52PubMedPubMedCentralCrossRefGoogle Scholar
  149. Singh KK, Desouki MM, Franklin RB, Costello LC (2006) Mitochondrial aconitase and citrate metabolism in malignant and nonmalignant human prostate tissues. Mol Cancer 5:14PubMedPubMedCentralCrossRefGoogle Scholar
  150. Sjursen W, Halvorsen H, Hofsli E, Bachke S, Berge A, Engebretsen LF, Falkmer SE, Falkmer UG, Varhaug JE (2013) Mutation screening in a Norwegian cohort with pheochromocytoma. Fam Cancer 12:529–535PubMedCrossRefGoogle Scholar
  151. Smit DL, Mensenkamp AR, Badeloe S, Breuning MH, Simon ME, van Spaendonck KY, Aalfs CM, Post JG, Shanley S, Krapels IP et al (2011) Hereditary leiomyomatosis and renal cell cancer in families referred for fumarate hydratase germline mutation analysis. Clin Genet 79:49–59PubMedCrossRefGoogle Scholar
  152. Snezhkina AV, Krasnov GS, Zaretsky AR, Zhavoronkov A, Nyushko KM, Moskalev AA, Karpova IY, Afremova AI, Lipatova AV, Kochetkov DV et al (2016) Differential expression of alternatively spliced transcripts related to energy metabolism in colorectal cancer. BMC Genomics 17:1011PubMedPubMedCentralCrossRefGoogle Scholar
  153. Stephen AG, Esposito D, Bagni RK, McCormick F (2014) Dragging ras back in the ring. Cancer Cell 25:272–281PubMedCrossRefGoogle Scholar
  154. Strohecker AM, White E (2014) Autophagy promotes BrafV600E-driven lung tumorigenesis by preserving mitochondrial metabolism. Autophagy 10:384–385PubMedCrossRefGoogle Scholar
  155. Stuart SD, Schauble A, Gupta S, Kennedy AD, Keppler BR, Bingham PM, Zachar Z (2014) A strategically designed small molecule attacks alpha-ketoglutarate dehydrogenase in tumor cells through a redox process. Cancer Metab 2:4PubMedPubMedCentralCrossRefGoogle Scholar
  156. Sullivan LB, Martinez-Garcia E, Nguyen H, Mullen AR, Dufour E, Sudarshan S, Licht JD, Deberardinis RJ, Chandel NS (2013) The proto-oncometabolite fumarate binds glutathione to amplify ROS-dependent signaling. Mol Cell 51:236–248PubMedPubMedCentralCrossRefGoogle Scholar
  157. Svensson RU, Shaw RJ (2017) Lipid synthesis is a metabolic liability of non-small cell lung cancer. In: Cold Spring Harbor symposia on quantitative biology. Cold Spring Harbor Laboratory Press, Cold Spring HarborGoogle Scholar
  158. Swinnen JV, Roskams T, Joniau S, Van Poppel H, Oyen R, Baert L, Heyns W, Verhoeven G (2002) Overexpression of fatty acid synthase is an early and common event in the development of prostate cancer. Int J Cancer 98:19–22PubMedCrossRefGoogle Scholar
  159. Taschner PE, Jansen JC, Baysal BE, Bosch A, Rosenberg EH, Brocker-Vriends AH, van Der Mey AG, van Ommen GJ, Cornelisse CJ, Devilee P (2001) Nearly all hereditary paragangliomas in the Netherlands are caused by two founder mutations in the SDHD gene. Genes Chromosomes Cancer 31:274–281PubMedCrossRefGoogle Scholar
  160. Tateishi K, Wakimoto H, Iafrate AJ, Tanaka S, Loebel F, Lelic N, Wiederschain D, Bedel O, Deng G, Zhang B et al (2015) Extreme vulnerability of IDH1 mutant cancers to NAD+ depletion. Cancer Cell 28:773–784PubMedPubMedCentralCrossRefGoogle Scholar
  161. Tomlinson IP, Alam NA, Rowan AJ, Barclay E, Jaeger EE, Kelsell D, Leigh I, Gorman P, Lamlum H, Rahman S et al (2002) Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet 30:406–410PubMedCrossRefGoogle Scholar
  162. Toro JR, Nickerson ML, Wei MH, Warren MB, Glenn GM, Turner ML, Stewart L, Duray P, Tourre O, Sharma N et al (2003) Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America. Am J Hum Genet 73:95–106PubMedPubMedCentralCrossRefGoogle Scholar
  163. Tufton N, Roncaroli F, Hadjidemetriou I, Dang MN, Denes J, Guasti L, Thom M, Powell M, Baldeweg SE, Fersht N et al (2017) Pituitary carcinoma in a patient with an SDHB mutation. Endocr Pathol. doi: 10.1007/s12022-017-9474-7 PubMedPubMedCentralGoogle Scholar
  164. Vanharanta S, Buchta M, McWhinney SR, Virta SK, Peczkowska M, Morrison CD, Lehtonen R, Januszewicz A, Jarvinen H, Juhola M et al (2004) Early-onset renal cell carcinoma as a novel extraparaganglial component of SDHB-associated heritable paraganglioma. Am J Hum Genet 74:153–159PubMedCrossRefGoogle Scholar
  165. Wahlstrom T, Henriksson MA (2015) Impact of MYC in regulation of tumor cell metabolism. Biochim Biophys Acta 1849:563–569PubMedCrossRefGoogle Scholar
  166. Wang R, Dillon CP, Shi LZ, Milasta S, Carter R, Finkelstein D, McCormick LL, Fitzgerald P, Chi H, Munger J et al (2011) The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity 35:871–882PubMedPubMedCentralCrossRefGoogle Scholar
  167. Wang P, Mai C, Wei YL, Zhao JJ, Hu YM, Zeng ZL, Yang J, Lu WH, Xu RH, Huang P (2013) Decreased expression of the mitochondrial metabolic enzyme aconitase (ACO2) is associated with poor prognosis in gastric cancer. Med Oncol 30:552PubMedCrossRefGoogle Scholar
  168. Wang MD, Wu H, Fu GB, Zhang HL, Zhou X, Tang L, Dong LW, Qin CJ, Huang S, Zhao LH et al (2016) Acetyl-coenzyme A carboxylase alpha promotion of glucose-mediated fatty acid synthesis enhances survival of hepatocellular carcinoma in mice and patients. Hepatology 63:1272–1286PubMedCrossRefGoogle Scholar
  169. Wang D, Yin L, Wei J, Yang Z, Jiang G (2017) ATP citrate lyase is increased in human breast cancer, depletion of which promotes apoptosis. Tumour Biol 39:1010428317698338PubMedGoogle Scholar
  170. Warburg O, Wind F, Negelein E (1927) The metabolism of tumors in the body. J Gen Physiol 8:519–530PubMedPubMedCentralCrossRefGoogle Scholar
  171. Ward PS, Thompson CB (2012) Signaling in control of cell growth and metabolism. Cold Spring Harb Perspect Biol 4:a006783PubMedPubMedCentralCrossRefGoogle Scholar
  172. Wei MH, Toure O, Glenn GM, Pithukpakorn M, Neckers L, Stolle C, Choyke P, Grubb R, Middelton L, Turner ML et al (2006) Novel mutations in FH and expansion of the spectrum of phenotypes expressed in families with hereditary leiomyomatosis and renal cell cancer. J Med Genet 43:18–27PubMedCrossRefGoogle Scholar
  173. Wise DR, DeBerardinis RJ, Mancuso A, Sayed N, Zhang XY, Pfeiffer HK, Nissim I, Daikhin E, Yudkoff M, McMahon SB et al (2008) Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc Natl Acad Sci U S A 105:18782–18787PubMedPubMedCentralCrossRefGoogle Scholar
  174. Wong MH, Tan CS, Lee SC, Yong Y, Ooi AS, Ngeow J, Tan MH (2014) Potential genetic anticipation in hereditary leiomyomatosis-renal cell cancer (HLRCC). Fam Cancer 13:281–289PubMedCrossRefGoogle Scholar
  175. Xin M, Qiao Z, Li J, Liu J, Song S, Zhao X, Miao P, Tang T, Wang L, Liu W et al (2016) miR-22 inhibits tumor growth and metastasis by targeting ATP citrate lyase: evidence in osteosarcoma, prostate cancer, cervical cancer and lung cancer. Oncotarget 7:44252–44265PubMedPubMedCentralCrossRefGoogle Scholar
  176. Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim SH, Ito S, Yang C, Wang P, Xiao MT et al (2011) Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases. Cancer Cell 19:17–30PubMedPubMedCentralCrossRefGoogle Scholar
  177. Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle I, Jones S, Riggins GJ et al (2009) IDH1 and IDH2 mutations in gliomas. N Engl J Med 360:765–773PubMedPubMedCentralCrossRefGoogle Scholar
  178. Yang Y, Lane AN, Ricketts CJ, Sourbier C, Wei MH, Shuch B, Pike L, Wu M, Rouault TA, Boros LG et al (2013) Metabolic reprogramming for producing energy and reducing power in fumarate hydratase null cells from hereditary leiomyomatosis renal cell carcinoma. PLoS ONE 8:e72179PubMedPubMedCentralCrossRefGoogle Scholar
  179. Yang M, Ternette N, Su H, Dabiri R, Kessler BM, Adam J, Teh BT, Pollard PJ (2014) The succinated proteome of FH-mutant tumours. Metabolites 4:640–654PubMedPubMedCentralCrossRefGoogle Scholar
  180. Yen KE, Bittinger MA, Su SM, Fantin VR (2010) Cancer-associated IDH mutations: biomarker and therapeutic opportunities. Oncogene 29:6409–6417PubMedCrossRefGoogle Scholar
  181. Yen K, Travins J, Wang F, David MD, Artin E, Straley K, Padyana A, Gross S, DeLaBarre B, Tobin E et al (2017) AG-221, a first-in-class therapy targeting acute myeloid leukemia harboring oncogenic IDH2 mutations. Cancer Discov 7(5):478–493PubMedCrossRefGoogle Scholar
  182. Ylisaukko-oja SK, Cybulski C, Lehtonen R, Kiuru M, Matyjasik J, Szymanska A, Szymanska-Pasternak J, Dyrskjot L, Butzow R, Orntoft TF et al (2006) Germline fumarate hydratase mutations in patients with ovarian mucinous cystadenoma. Eur J Hum Genet 14:880–883PubMedCrossRefGoogle Scholar
  183. Yuneva MO, Fan TW, Allen TD, Higashi RM, Ferraris DV, Tsukamoto T, Mates JM, Alonso FJ, Wang C, Seo Y et al (2012) The metabolic profile of tumors depends on both the responsible genetic lesion and tissue type. Cell Metab 15:157–170PubMedPubMedCentralCrossRefGoogle Scholar
  184. Zachar Z, Marecek J, Maturo C, Gupta S, Stuart SD, Howell K, Schauble A, Lem J, Piramzadian A, Karnik S et al (2011) Non-redox-active lipoate derivates disrupt cancer cell mitochondrial metabolism and are potent anticancer agents in vivo. J Mol Med (Berl) 89:1137–1148CrossRefGoogle Scholar
  185. Zantour B, Guilhaume B, Tissier F, Louvel A, Jeunemaitre X, Gimenez-Roqueplo AP, Bertagna X (2004) A thyroid nodule revealing a paraganglioma in a patient with a new germline mutation in the succinate dehydrogenase B gene. Eur J Endocrinol 151:433–438PubMedCrossRefGoogle Scholar
  186. Zhang C, Lin M, Wu R, Wang X, Yang B, Levine AJ, Hu W, Feng Z (2011) Parkin, a p53 target gene, mediates the role of p53 in glucose metabolism and the Warburg effect. Proc Natl Acad Sci USA 108:16259–16264PubMedPubMedCentralCrossRefGoogle Scholar
  187. Zhang Y, Wei H, Tang K, Lin D, Zhang C, Mi Y, Wang L, Wang C, Wang M, Wang J (2012) Mutation analysis of isocitrate dehydrogenase in acute lymphoblastic leukemia. Genet Test Mol Biomark 16:991–995CrossRefGoogle Scholar
  188. Zhang C, Liu J, Liang Y, Wu R, Zhao Y, Hong X, Lin M, Yu H, Liu L, Levine AJ et al (2013) Tumour-associated mutant p53 drives the Warburg effect. Nat Commun 4:2935PubMedPubMedCentralGoogle Scholar
  189. Zugazagoitia J, Guedes C, Ponce S, Ferrer I, Molina-Pinelo S, Paz-Ares L (2016) Current challenges in cancer treatment. Clin Ther 38:1551–1566PubMedCrossRefGoogle Scholar

Copyright information

© The Author(s) 2017

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Authors and Affiliations

  • Nicole M. Anderson
    • 1
    • 2
  • Patrick Mucka
    • 3
  • Joseph G. Kern
    • 4
  • Hui Feng
    • 3
    Email author
  1. 1.Abramson Family Cancer Research InstituteUniversity of PennsylvaniaPhiladelphiaUSA
  2. 2.Perelman School of Medicine at the University of PennsylvaniaPhiladelphiaUSA
  3. 3.Departments of Pharmacology and Medicine, The Center for Cancer Research, Section of Hematology and Medical OncologyBoston University School of MedicineBostonUSA
  4. 4.Program in Biomedical SciencesBoston University School of MedicineBostonUSA

Personalised recommendations