Metabolic Remodeling as a Way of Adapting to Tumor Microenvironment (TME), a Job of Several Holders

  • Jacinta SerpaEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1219)


The microenvironment depends and generates dependence on all the cells and structures that share the same niche, the biotope. The contemporaneous view of the tumor microenvironment (TME) agrees with this idea. The cells that make up the tumor, whether malignant or not, behave similarly to classes of elements within a living community. These elements inhabit, modify and benefit from all the facilities the microenvironment has to offer and that will contribute to the survival and growth of the tumor and the progression of the disease.

The metabolic adaptation to microenvironment is a crucial process conducting to an established tumor able to grow locally, invade and metastasized. The metastatic cancer cells are reasonable more plastic than non-metastatic cancer cells, because the previous ones must survive in the microenvironment where the primary tumor develops and in addition, they must prosper in the microenvironment in the metastasized organ.

The metabolic remodeling requires not only the adjustment of metabolic pathways per se but also the readjustment of signaling pathways that will receive and obey to the extracellular instructions, commanding the metabolic adaptation. Many diverse players are pivotal in cancer metabolic fitness from the initial signaling stimuli, going through the activation or repression of genes, until the phenotype display. The new phenotype will permit the import and consumption of organic compounds, useful for energy and biomass production, and the export of metabolic products that are useless or must be secreted for a further recycling or controlled uptake. In the metabolic network, three subsets of players are pivotal: (1) the organic compounds; (2) the transmembrane transporters, and (3) the enzymes.

This chapter will present the “Pharaonic” intent of diagraming the interplay between these three elements in an attempt of simplifying and, at the same time, of showing the complex sight of cancer metabolism, addressing the orchestrating role of microenvironment and highlighting the influence of non-cancerous cells.


Cancer cell metabolism Metabolic network Metabolic remodeling Tumor microenvironment (TME) Glycolysis Pentose phosphate pathway (PPP) Glutaminolysis Fatty acids synthesis β-oxidation One-carbon metabolism Transsulfuration pathway (TSSP) 



The authors acknowledge iNOVA4Health – UID/Multi/04462/2013, a program financially supported by Fundação para a Ciência e Tecnologia/Ministério da Educação e Ciência, through national funds and co-funded by FEDER under the PT2020 Partnership Agreement.


  1. Adeva-Andany MM et al (2019) Mitochondrial β-oxidation of saturated fatty acids in humans. Mitochondrion 46:73–90PubMedCrossRefGoogle Scholar
  2. Afonso J et al (2019) Clinical significance of metabolism-related biomarkers in non-Hodgkin lymphoma – MCT1 as potential target in diffuse large B cell lymphoma. Cell Oncol 42:303–318CrossRefGoogle Scholar
  3. Aiderus A et al (2018) Fatty acid oxidation is associated with proliferation and prognosis in breast and other cancers. BMC Cancer 18:805–805PubMedPubMedCentralCrossRefGoogle Scholar
  4. Al-Alem LF et al (2013) Activation of the PKC pathway stimulates ovarian cancer cell proliferation, migration, and expression of MMP7 and MMP10. Biol Reprod 89:73–73PubMedPubMedCentralCrossRefGoogle Scholar
  5. Alam MM et al (2016) A holistic view of cancer bioenergetics: mitochondrial function and respiration play fundamental roles in the development and progression of diverse tumors. Clin Transl Med 5:3–3PubMedPubMedCentralCrossRefGoogle Scholar
  6. Alix-Panabières C et al (2017) Molecular portrait of metastasis-competent circulating tumor cells in colon cancer reveals the crucial role of genes regulating Energy metabolism and DNA repair. Clin Chem 63:700–713PubMedCrossRefGoogle Scholar
  7. Allen E et al (2016) Metabolic symbiosis enables adaptive resistance to anti-angiogenic therapy that is dependent on mTOR signaling. Cell Rep 15:1144–1160PubMedPubMedCentralCrossRefGoogle Scholar
  8. Altman BJ et al (2016) From Krebs to clinic: glutamine metabolism to cancer therapy. Nat Rev Cancer 16:619–634PubMedPubMedCentralCrossRefGoogle Scholar
  9. Amelio I et al (2014) Serine and glycine metabolism in cancer. Trends Biochem Sci 39:191–198PubMedPubMedCentralCrossRefGoogle Scholar
  10. Amrita Devi K et al (2015) ATP Citrate Lyase (ACLY): a promising target for cancer prevention and treatment. Curr Drug Targets 16:156–163CrossRefGoogle Scholar
  11. Anastasiou D et al (2011) Inhibition of pyruvate kinase M2 by reactive oxygen species contributes to cellular antioxidant responses. Science 334:1278–1283PubMedPubMedCentralCrossRefGoogle Scholar
  12. Andersen S et al (2015) Organized metabolic crime in prostate cancer: the coexpression of MCT1 in tumor and MCT4 in stroma is an independent prognosticator for biochemical failure. Urol Oncol Semin Orig Investig 33:338.e339–338.e317Google Scholar
  13. Anderson CM, Stahl A (2013) SLC27 fatty acid transport proteins. Mol Asp Med 34:516–528CrossRefGoogle Scholar
  14. Ando M et al (2010) Interleukin 6 enhances Glycolysis through expression of the Glycolytic enzymes Hexokinase 2 and 6-Phosphofructo-2-kinase/Fructose-2,6-bisphosphatase-3. J Nippon Med Sch 77:97–105PubMedCrossRefGoogle Scholar
  15. Asukai K et al (2017) Micro-RNA-130a-3p regulates Gemcitabine resistance via PPARG in Cholangiocarcinoma. Ann Surg Oncol 24:2344–2352PubMedCrossRefGoogle Scholar
  16. Augsburger F, Szabo C (2018) Potential role of the 3-mercaptopyruvate sulfurtransferase (3-MST)—hydrogen sulfide (H2S) pathway in cancer cells. Pharmacol Res 104083Google Scholar
  17. Augsten M (2014) Cancer-associated fibroblasts as another polarized cell type of the tumor microenvironment. Front Oncol 4:62PubMedPubMedCentralCrossRefGoogle Scholar
  18. Azar S et al (2018) Cellular and molecular characterization of IDH1-mutated diffuse low grade gliomas reveals tumor heterogeneity and absence of EGFR/PDGFRα activation. Glia 66:239–255PubMedCrossRefGoogle Scholar
  19. Baek G et al (2014) MCT4 defines a glycolytic subtype of pancreatic cancer with poor prognosis and unique metabolic dependencies. Cell Rep 9:2233–2249PubMedCrossRefGoogle Scholar
  20. Balaban S et al (2017) Adipocyte lipolysis links obesity to breast cancer growth: adipocyte-derived fatty acids drive breast cancer cell proliferation and migration. Cancer Metab 5:1PubMedPubMedCentralCrossRefGoogle Scholar
  21. Ballatori N et al (2009) Glutathione dysregulation and the etiology and progression of human diseases. Biol Chem 390:191–214PubMedPubMedCentralCrossRefGoogle Scholar
  22. Beckner ME et al (2010) Identification of ATP citrate lyase as a positive regulator of glycolytic function in glioblastomas. Int J Cancer 126:2282–2295PubMedPubMedCentralGoogle Scholar
  23. Bhattacharyya S et al (2013) Cystathionine beta-synthase (CBS) contributes to advanced ovarian cancer progression and drug resistance. PLoS One 8:e79167–e79167PubMedPubMedCentralCrossRefGoogle Scholar
  24. Bhutia YD, Ganapathy V (2016) Glutamine transporters in mammalian cells and their functions in physiology and cancer. Biochim Biophys Acta 1863:2531–2539PubMedCrossRefGoogle Scholar
  25. Bianchi MG et al (2012) Valproic acid induces the glutamate transporter excitatory amino acid transporter-3 in human oligodendroglioma cells. Neuroscience 227:260–270PubMedCrossRefGoogle Scholar
  26. Bianchi MG et al (2014) Changes in the expression of the glutamate transporter EAAT3/EAAC1 in health and disease. Cell Mol Life Sci 71:2001–2015PubMedCrossRefGoogle Scholar
  27. Biancur DE et al (2017) Compensatory metabolic networks in pancreatic cancers upon perturbation of glutamine metabolism. Nat Commun 8:15965–15965PubMedPubMedCentralCrossRefGoogle Scholar
  28. Bidkhori G et al (2018) Metabolic network-based stratification of hepatocellular carcinoma reveals three distinct tumor subtypes. Proc Natl Acad Sci U S A 115:E11874–E11883PubMedPubMedCentralCrossRefGoogle Scholar
  29. Boidot R et al (2012) Regulation of Monocarboxylate transporter MCT1 expression by p53 mediates inward and outward lactate fluxes in tumors. Cancer Res 72:939–948PubMedCrossRefGoogle Scholar
  30. Bolzoni M et al (2016) Dependence on glutamine uptake and glutamine addiction characterize myeloma cells: a new attractive target. Blood 128:667–679PubMedCrossRefGoogle Scholar
  31. Bonito CA et al (2016) Insights into medium-chain Acyl-CoA dehydrogenase structure by molecular dynamics simulations. Chem Biol Drug Des 88:281–292PubMedCrossRefGoogle Scholar
  32. Bothwell PJ et al (2018) Targeted suppression and knockout of ASCT2 or LAT1 in epithelial and mesenchymal human liver cancer cells fail to inhibit growth. Int J Mol Sci 19:2093PubMedCentralCrossRefPubMedGoogle Scholar
  33. Bourbeau MP, Bartberger MD (2015) Recent advances in the development of Acetyl-CoA Carboxylase (ACC) inhibitors for the treatment of Metabolic disease. J Med Chem 58:525–536PubMedCrossRefGoogle Scholar
  34. Bräutigam K et al (2011) Combined treatment with TRAIL and PPARγ ligands overcomes chemoresistance of ovarian cancer cell lines. J Cancer Res Clin Oncol 137:875–886PubMedCrossRefGoogle Scholar
  35. Bröer A et al (2018) Disruption of amino acid homeostasis by novel ASCT2 inhibitors involves multiple targets. Front Pharmacol 9:785–785PubMedPubMedCentralCrossRefGoogle Scholar
  36. Bröer A et al (2019) Ablation of the ASCT2 (SLC1A5) gene encoding a neutral amino acid transporter reveals transporter plasticity and redundancy in cancer cells. J Biol Chem 294:4012–4026PubMedCrossRefGoogle Scholar
  37. Bruntz RC et al (2019) Inhibition of anaplerotic glutaminolysis underlies selenite toxicity in human lung cancer. Proteomics 0:1800486CrossRefGoogle Scholar
  38. Bryant KL et al (2014) KRAS: feeding pancreatic cancer proliferation. Trends Biochem Sci 39:91–100PubMedPubMedCentralCrossRefGoogle Scholar
  39. Cabrera R et al (2011) The crystal complex of phosphofructokinase-2 of Escherichia coli with fructose-6-phosphate: kinetic and structural analysis of the allosteric ATP inhibition. J Biol Chem 286:5774–5783PubMedCrossRefGoogle Scholar
  40. Calvert AE et al (2017) Cancer-associated IDH1 promotes growth and resistance to targeted therapies in the absence of mutation. Cell Rep 19:1858–1873PubMedPubMedCentralCrossRefGoogle Scholar
  41. Cao A et al (2010) Long chain acyl-CoA synthetase-3 is a molecular target for peroxisome proliferator-activated receptor delta in HepG2 hepatoma cells. J Biol Chem 285:16664–16674PubMedPubMedCentralCrossRefGoogle Scholar
  42. Carduner L et al (2014) Cell cycle arrest or survival signaling through αv integrins, activation of PKC and ERK1/2 lead to anoikis resistance of ovarian cancer spheroids. Exp Cell Res 320:329–342PubMedCrossRefGoogle Scholar
  43. Carneiro L, Pellerin L (2015) Monocarboxylate transporters: new players in body weight regulation. Obes Rev 16:55–66PubMedCrossRefGoogle Scholar
  44. Carr EL et al (2010) Glutamine uptake and metabolism are coordinately regulated by ERK/MAPK during T lymphocyte activation. J Immunol 185:1037–1044PubMedPubMedCentralCrossRefGoogle Scholar
  45. Carracedo A et al (2013) Cancer metabolism: fatty acid oxidation in the limelight. Nat Rev Cancer 13:227–232PubMedPubMedCentralCrossRefGoogle Scholar
  46. Carrer A, Wellen KE (2015) Metabolism and epigenetics: a link cancer cells exploit. Curr Opin Biotechnol 34:23–29PubMedCrossRefGoogle Scholar
  47. Carrer A et al (2017) Impact of a high-fat diet on tissue Acyl-CoA and histone acetylation levels. J Biol Chem 292:3312–3322PubMedPubMedCentralCrossRefGoogle Scholar
  48. Carrer A et al (2019) Acetyl-CoA metabolism supports multistep pancreatic tumorigenesis. Cancer Discov 9:416–435PubMedPubMedCentralCrossRefGoogle Scholar
  49. Carter JC, Church FC (2012) Mature breast adipocytes promote breast cancer cell motility. Exp Mol Pathol 92:312–317PubMedCrossRefGoogle Scholar
  50. Catalina-Rodriguez O et al (2012) The mitochondrial citrate transporter, CIC, is essential for mitochondrial homeostasis. Oncotarget 3:1220–1235PubMedPubMedCentralCrossRefGoogle Scholar
  51. Chang C-I et al (2001) Macrophage arginase promotes tumor cell growth and suppresses nitric oxide-mediated tumor cytotoxicity. Cancer Res 61:1100–1106PubMedGoogle Scholar
  52. Chen L, Cui H (2015) Targeting glutamine induces apoptosis: a cancer therapy approach. Int J Mol Sci 16:22830–22855PubMedPubMedCentralCrossRefGoogle Scholar
  53. Chen K et al (2014) Integrative metabolome and transcriptome profiling reveals discordant glycolysis process between osteosarcoma and normal osteoblastic cells. J Cancer Res Clin Oncol 140:1715–1721PubMedCrossRefGoogle Scholar
  54. Chen J et al (2019a) SIRT1 promotes GLUT1 expression and bladder cancer progression via regulation of glucose uptake. Hum Cell 32:193–201PubMedCrossRefGoogle Scholar
  55. Chen F et al (2019b) Extracellular vesicle-packaged HIF-1α-stabilizing lncRNA from tumour-associated macrophages regulates aerobic glycolysis of breast cancer cells. Nat Cell Biol 21:498–510PubMedCrossRefGoogle Scholar
  56. Cho H et al (2013) Overexpression of glucose transporter-1 (GLUT-1) predicts poor prognosis in epithelial ovarian cancer. Cancer Investig 31:607–615CrossRefGoogle Scholar
  57. Choi J et al (2015) Glioblastoma cells induce differential glutamatergic gene expressions in human tumor-associated microglia/macrophages and monocyte-derived macrophages. Cancer Biol Ther 16:1205–1213PubMedPubMedCentralCrossRefGoogle Scholar
  58. Coffelt SB et al (2009) Tumor-associated macrophages: effectors of angiogenesis and tumor progression. Biochimica et Biophysica Acta (BBA) – Rev Cancer 1796:11–18CrossRefGoogle Scholar
  59. Colla R et al (2016) Glutathione-mediated antioxidant response and aerobic metabolism: two crucial factors involved in determining the multi-drug resistance of high-risk neuroblastoma. Oncotarget 7:70715–70737PubMedPubMedCentralCrossRefGoogle Scholar
  60. Combs JA, De Nicola GM (2019) The non-essential amino acid cysteine becomes essential for tumor proliferation and survival. Cancers (Basel) 11:678CrossRefGoogle Scholar
  61. Corbet C, Feron O (2017) Cancer cell metabolism and mitochondria: nutrient plasticity for TCA cycle fueling. Biochimica et Biophysica Acta (BBA) – Rev Cancer 1868:7–15CrossRefGoogle Scholar
  62. Corbet C et al (2016) Acidosis drives the reprogramming of fatty acid metabolism in cancer cells through changes in mitochondrial and histone acetylation. Cell Metab 24:311–323PubMedPubMedCentralCrossRefGoogle Scholar
  63. Cui H et al (2007) Enhanced expression of asparagine synthetase under glucose-deprived conditions protects pancreatic cancer cells from apoptosis induced by glucose deprivation and cisplatin. Cancer Res 67:3345–3355PubMedCrossRefGoogle Scholar
  64. Currie E et al (2013) Cellular fatty acid metabolism and cancer. Cell Metab 18:153–161PubMedPubMedCentralCrossRefGoogle Scholar
  65. Curry JM et al (2013) Cancer metabolism, stemness and tumor recurrence: MCT1 and MCT4 are functional biomarkers of metabolic symbiosis in head and neck cancer. Cell Cycle (Georgetown Tex) 12:1371–1384CrossRefGoogle Scholar
  66. D’Esposito V et al (2012) Adipocyte-released insulin-like growth factor-1 is regulated by glucose and fatty acids and controls breast cancer cell growth in vitro. Diabetologia 55:2811–2822PubMedPubMedCentralCrossRefGoogle Scholar
  67. DeBerardinis RJ et al (2007) Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc Natl Acad Sci U S A 104:19345–19350PubMedPubMedCentralCrossRefGoogle Scholar
  68. DeClerck YA (2012) Desmoplasia: a response or a Niche? Cancer Discov 2:772–774PubMedCrossRefGoogle Scholar
  69. Dijkgraaf EM et al (2013) Chemotherapy alters monocyte differentiation to favor generation of cancer-supporting M2 macrophages in the tumor microenvironment. Cancer Res 73:2480–2492PubMedCrossRefGoogle Scholar
  70. Ding W et al (2010) Platelet-derived growth factor (PDGF)–PDGF receptor interaction activates bone marrow–derived mesenchymal stromal cells derived from chronic lymphocytic leukemia: implications for an angiogenic switch. Blood 116:2984–2993PubMedPubMedCentralCrossRefGoogle Scholar
  71. Dirat B et al (2011) Cancer-associated adipocytes exhibit an activated phenotype and contribute to Breast cancer invasion. Cancer Res 71:2455–2465CrossRefGoogle Scholar
  72. Do SK et al (2019) Glucose transporter 3 gene variant is associated with survival outcome of patients with non-small cell lung cancer after surgical resection. Gene 703:58–64PubMedCrossRefGoogle Scholar
  73. Dodo M et al (2018) Lactate dehydrogenase C is required for the protein expression of a sperm-specific isoform of lactate dehydrogenase A. J Biochem 165:323–334CrossRefGoogle Scholar
  74. Doherty JR et al (2014) Blocking lactate export by inhibiting the myc target MCT1 Disables glycolysis and glutathione synthesis. Cancer Res 74:908–920PubMedCrossRefGoogle Scholar
  75. Dornier E et al (2017) Glutaminolysis drives membrane trafficking to promote invasiveness of breast cancer cells. Nat Commun 8:2255–2255PubMedPubMedCentralCrossRefGoogle Scholar
  76. Doxsee DW et al (2007) Sulfasalazine-induced cystine starvation: potential use for prostate cancer therapy. Prostate 67:162–171PubMedCrossRefGoogle Scholar
  77. Drayton RM et al (2014) Reduced expression of miRNA-27a modulates cisplatin resistance in bladder cancer by targeting the cystine/glutamate exchanger SLC7A11. Clin Cancer Res 20:1990–2000PubMedPubMedCentralCrossRefGoogle Scholar
  78. Drew BG et al (2015) Estrogen receptor (ER)α-regulated lipocalin 2 expression in adipose tissue links obesity with breast cancer progression. J Biol Chem 290:5566–5581CrossRefGoogle Scholar
  79. Du Q et al (2019) PGC1α/CEBPB/CPT1A axis promotes radiation resistance of nasopharyngeal carcinoma through activating fatty acid oxidation. Cancer Sci 110:2050–2062PubMedPubMedCentralGoogle Scholar
  80. Ducker GS et al (2017) Human SHMT inhibitors reveal defective glycine import as a targetable metabolic vulnerability of diffuse large B-cell lymphoma. Proc Natl Acad Sci U S A 114:11404–11409PubMedPubMedCentralCrossRefGoogle Scholar
  81. Dufour E et al (2012) Pancreatic tumor sensitivity to plasma L-Asparagine starvation. Pancreas 41:940–948PubMedCrossRefGoogle Scholar
  82. Echevarría-Vargas IM et al (2014) Upregulation of miR-21 in cisplatin resistant ovarian cancer via JNK-1/c-Jun pathway. PLoS One 9:e97094–e97094PubMedPubMedCentralCrossRefGoogle Scholar
  83. Elhanati S et al (2013) Multiple regulatory layers of SREBP1/2 by SIRT6. Cell Rep 4:905–912PubMedCrossRefGoogle Scholar
  84. Emmanuel C et al (2014) Genomic classification of serous ovarian cancer with adjacent borderline differentiates RAS pathway and TP53-mutant tumors and identifies NRAS as an oncogenic driver. Clin Cancer Res 20:6618–6630Google Scholar
  85. Enciu A-M et al (2018) Targeting CD36 as biomarker for metastasis prognostic: how far from translation into clinical practice? Biomed Res Int 2018:7801202–7801202PubMedPubMedCentralCrossRefGoogle Scholar
  86. Eng CH et al (2010) Ammonia derived from glutaminolysis is a diffusible regulator of autophagy. Sci Signal 3:ra31–ra31PubMedGoogle Scholar
  87. Fazzari J et al (2015) Inhibitors of glutamate release from breast cancer cells; new targets for cancer-induced bone-pain. Sci Rep 5:8380–8380PubMedPubMedCentralCrossRefGoogle Scholar
  88. Feng M et al (2018) LAT2 regulates glutamine-dependent mTOR activation to promote glycolysis and chemoresistance in pancreatic cancer. J Exp Clin Cancer Res 37:274–274PubMedPubMedCentralCrossRefGoogle Scholar
  89. Fernandes LM et al (2018) Malic enzyme 1 (ME1) is pro-oncogenic in Apc(Min/+) mice. Sci Rep 8:14268–14268PubMedPubMedCentralCrossRefGoogle Scholar
  90. Fiaschi T et al (2012) Reciprocal metabolic reprogramming through lactate shuttle coordinately influences tumor-stroma interplay. Cancer Res 72:5130–5140PubMedCrossRefGoogle Scholar
  91. Fisher RM, Gertow K (2005) Fatty acid transport proteins and insulin resistance. Curr Opin Lipidol 16:173–178PubMedCrossRefGoogle Scholar
  92. Frey IM et al (2007) Profiling at mRNA, protein, and metabolite levels reveals alterations in renal amino acid handling and glutathione metabolism in kidney tissue of Pept2−/− mice. Physiol Genomics 28:301–310PubMedCrossRefGoogle Scholar
  93. Fu M et al (2012) Hydrogen sulfide (H2S) metabolism in mitochondria and its regulatory role in energy production. Proc Natl Acad Sci U S A 109:2943–2948PubMedPubMedCentralCrossRefGoogle Scholar
  94. Fujii S et al (2019) Persulfide synthases that are functionally coupled with translation mediate sulfur respiration in mammalian cells. Br J Pharmacol 176:607–615PubMedCrossRefGoogle Scholar
  95. Fujino M et al (2016) Expression of glucose transporter-1 is correlated with hypoxia-inducible factor 1α and malignant potential in pancreatic neuroendocrine tumors. Oncol Lett 12:3337–3343PubMedPubMedCentralCrossRefGoogle Scholar
  96. Fujisaki K et al (2015) Cancer-mediated adipose reversion promotes cancer cell migration via IL-6 and MCP-1. Breast Cancer Res Treat 150:255–263PubMedCrossRefGoogle Scholar
  97. Fujiwara N et al (2018) CPT2 downregulation adapts HCC to lipid-rich environment and promotes carcinogenesis via acylcarnitine accumulation in obesity. Gut 67:1493–1504PubMedPubMedCentralCrossRefGoogle Scholar
  98. Fukuda S et al (2015) Pyruvate Kinase M2 modulates esophageal squamous cell carcinoma chemotherapy response by regulating the pentose phosphate pathway. Ann Surg Oncol 22:1461–1468CrossRefGoogle Scholar
  99. Gaglio D et al (2011) Oncogenic K-Ras decouples glucose and glutamine metabolism to support cancer cell growth. Mol Syst Biol 7:523–523PubMedPubMedCentralCrossRefGoogle Scholar
  100. Gai J-W et al (2016) Expression profile of hydrogen sulfide and its synthases correlates with tumor stage and grade in urothelial cell carcinoma of bladder. Urol Oncol Semin Orig Investig 34:166.e115–166.e120Google Scholar
  101. Galan-Cobo A et al (2019) LKB1 and KEAP1/NRF2 pathways cooperatively promote metabolic reprogramming with enhanced glutamine dependence in <em>KRAS</em>-mutant lung adenocarcinoma. Cancer Res 79:3251–3267PubMedCrossRefGoogle Scholar
  102. Gào X, Schöttker B (2017) Reduction-oxidation pathways involved in cancer development: a systematic review of literature reviews. Oncotarget 8:51888–51906PubMedPubMedCentralGoogle Scholar
  103. Gao P et al (2009) c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature 458:762–765PubMedPubMedCentralCrossRefGoogle Scholar
  104. Gao Y et al (2017) TNFα-YAP/p65-HK2 axis mediates breast cancer cell migration. Oncogene 6:e383–e383CrossRefGoogle Scholar
  105. Gillies RJ, Gatenby RA (2015) Metabolism and its sequelae in cancer evolution and therapy. Cancer J 21:88–96PubMedPubMedCentralCrossRefGoogle Scholar
  106. Giuffrè A, Vicente JB (2018) Hydrogen sulfide biochemistry and interplay with other gaseous mediators in mammalian physiology. Oxidative Med Cell Longev 2018:6290931–6290931CrossRefGoogle Scholar
  107. Giuliani N et al (2017) The potential of inhibiting glutamine uptake as a therapeutic target for multiple myeloma. Expert Opin Ther Targets 21:231–234PubMedCrossRefGoogle Scholar
  108. Gordon S, Taylor PR (2005) Monocyte and macrophage heterogeneity. Nat Rev Immunol 5:953–964PubMedPubMedCentralCrossRefGoogle Scholar
  109. Grasmann G et al (2019) Gluconeogenesis in cancer cells – repurposing of a starvation-induced metabolic pathway? Biochimica et Biophysica Acta (BBA) – Rev Cancer 1872:24–36CrossRefGoogle Scholar
  110. Gregory MA et al (2019) Targeting glutamine metabolism and Redox state for Leukemia therapy. Clin Cancer Res 25:4079–4090PubMedCrossRefGoogle Scholar
  111. Grisouard J et al (2011) Targeting AMP-activated protein kinase in adipocytes to modulate obesity-related adipokine production associated with insulin resistance and breast cancer cell proliferation. Diabetol Metab Syndr 3:16–16PubMedPubMedCentralCrossRefGoogle Scholar
  112. Gu Y et al (2017) mTORC2 regulates amino acid metabolism in cancer by phosphorylation of the cystine-glutamate antiporter xCT. Mol Cell 67:128–138.e127PubMedPubMedCentralCrossRefGoogle Scholar
  113. Guaita-Esteruelas S et al (2017) Adipose-derived fatty acid-binding proteins plasma concentrations are increased in Breast cancer patients. Oncologist 22:1309–1315PubMedPubMedCentralCrossRefGoogle Scholar
  114. Gui DY et al (2013) Allosteric regulation of PKM2 allows cellular adaptation to different physiological states. Science Signal 6:pe7–pe7CrossRefGoogle Scholar
  115. Guido C et al (2012) Mitochondrial fission induces glycolytic reprogramming in cancer-associated myofibroblasts, driving stromal lactate production, and early tumor growth. Oncotarget 3:798–810PubMedPubMedCentralCrossRefGoogle Scholar
  116. Guppy M et al (2002) Contribution by different fuels and metabolic pathways to the total ATP turnover of proliferating MCF-7 breast cancer cells. Biochem J 364:309–315PubMedPubMedCentralCrossRefGoogle Scholar
  117. Gurrapu S et al (2015) Monocarboxylate transporter 1 inhibitors as potential anticancer agents. ACS Med Chem Lett 6:558–561PubMedPubMedCentralCrossRefGoogle Scholar
  118. Habib E et al (2015) Expression of xCT and activity of system xc(-) are regulated by NRF2 in human breast cancer cells in response to oxidative stress. Redox Biol 5:33–42PubMedPubMedCentralCrossRefGoogle Scholar
  119. Hajiahmadi S et al (2015) Activation of A2b adenosine receptor regulates ovarian cancer cell growth: involvement of Bax/Bcl-2 and caspase-3. Biochem Cell Biol 93:321–329PubMedCrossRefGoogle Scholar
  120. Halestrap AP (2013) The SLC16 gene family – structure, role and regulation in health and disease. Mol Asp Med 34:337–349CrossRefGoogle Scholar
  121. Hamann I et al (2018) Expression and function of hexose transporters GLUT1, GLUT2, and GLUT5 in breast cancer—effects of hypoxia. FASEB J 32:5104–5118PubMedCrossRefGoogle Scholar
  122. Hanai J-I et al (2012) Inhibition of lung cancer growth: ATP citrate lyase knockdown and statin treatment leads to dual blockade of mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K)/AKT pathways. J Cell Physiol 227:1709–1720PubMedPubMedCentralCrossRefGoogle Scholar
  123. Harris IS et al (2015) Glutathione and thioredoxin antioxidant pathways synergize to drive cancer initiation and progression. Cancer Cell 27:211–222PubMedCrossRefGoogle Scholar
  124. Hausheer FH et al (2011) Mechanistic study of BNP7787-mediated cisplatin nephroprotection: modulation of human aminopeptidase N. Cancer Chemother Pharmacol 67:381–391PubMedCrossRefGoogle Scholar
  125. Hensley CT et al (2013) Glutamine and cancer: cell biology, physiology, and clinical opportunities. J Clin Invest 123:3678–3684PubMedPubMedCentralCrossRefGoogle Scholar
  126. Hernández-Juárez J et al (2019) Sodium-coupled monocarboxylate transporter is a target of epigenetic repression in cervical cancer. Int J Oncol 54:1613–1624PubMedPubMedCentralGoogle Scholar
  127. Hlouschek J et al (2018) The mitochondrial citrate carrier (SLC25A1) sustains redox homeostasis and mitochondrial metabolism supporting radioresistance of cancer cells with tolerance to cycling severe hypoxia. Front Oncol 8:170PubMedPubMedCentralCrossRefGoogle Scholar
  128. Hong X et al (2014) PTEN antagonises Tcl1/hnRNPK-mediated G6PD pre-mRNA splicing which contributes to hepatocarcinogenesis. Gut 63:1635–1647PubMedCrossRefGoogle Scholar
  129. Hong SM et al (2019) Lactic acidosis caused by repressed lactate dehydrogenase subunit B expression down-regulates mitochondrial oxidative phosphorylation via the pyruvate dehydrogenase (PDH)-PDH kinase axis. J Biol Chem 294:7810–7820PubMedCrossRefGoogle Scholar
  130. Hopperton KE et al (2014) Fatty acid synthase plays a role in cancer metabolism beyond providing fatty acids for phospholipid synthesis or sustaining elevations in glycolytic activity. Exp Cell Res 320:302–310PubMedCrossRefGoogle Scholar
  131. Hou Z et al (2011) Macrophages induce COX-2 expression in breast cancer cells: role of IL-1β autoamplification. Carcinogenesis 32:695–702PubMedPubMedCentralCrossRefGoogle Scholar
  132. Hua TNM et al (2019) Inhibition of oncogenic Src induces FABP4-mediated lipolysis via PPARγ activation exerting cancer growth suppression. EBioMedicine 41:134–145PubMedPubMedCentralCrossRefGoogle Scholar
  133. Huang D et al (2014) HIF-1-mediated suppression of Acyl-CoA dehydrogenases and fatty acid oxidation is critical for cancer progression. Cell Rep 8:1930–1942PubMedCrossRefGoogle Scholar
  134. Hung YP, Yellen G (2014) Live-cell imaging of cytosolic NADH-NAD+ redox state using a genetically encoded fluorescent biosensor. Methods Mol Biol 1071:83–95PubMedPubMedCentralCrossRefGoogle Scholar
  135. Hung YP et al (2011) Imaging cytosolic NADH-NAD(+) redox state with a genetically encoded fluorescent biosensor. Cell Metab 14:545–554PubMedPubMedCentralCrossRefGoogle Scholar
  136. Hwang RF et al (2008) Cancer-associated stromal fibroblasts promote pancreatic tumor progression. Cancer Res 68:918–926PubMedPubMedCentralCrossRefGoogle Scholar
  137. Iershov A et al (2019) The class 3 PI3K coordinates autophagy and mitochondrial lipid catabolism by controlling nuclear receptor PPARα. Nat Commun 10:1566–1566PubMedPubMedCentralCrossRefGoogle Scholar
  138. Infantino V et al (2014) A key role of the mitochondrial citrate carrier (SLC25A1) in TNFα- and IFNγ-triggered inflammation. Biochim Biophys Acta 1839:1217–1225PubMedPubMedCentralCrossRefGoogle Scholar
  139. Israelsen WJ et al (2013) PKM2 isoform-specific deletion reveals a differential requirement for pyruvate kinase in tumor cells. Cell 155:397–409PubMedCrossRefGoogle Scholar
  140. Iwamoto M et al (2014) Regulation of 18F-FDG accumulation in colorectal cancer cells with mutated KRAS. J Nucl Med 55:2038–2044PubMedCrossRefGoogle Scholar
  141. Iwasaki K et al (2015) Role of hypoxia-inducible factor-1α, carbonic anhydrase-IX, glucose transporter-1 and vascular endothelial growth factor associated with lymph node metastasis and recurrence in patients with locally advanced cervical cancer. Oncol Lett 10:1970–1978PubMedPubMedCentralCrossRefGoogle Scholar
  142. Ji X et al (2018) xCT (SLC7A11)-mediated metabolic reprogramming promotes non-small cell lung cancer progression. Oncogene 37:5007–5019PubMedPubMedCentralCrossRefGoogle Scholar
  143. Jia D et al (2019) Elucidating cancer metabolic plasticity by coupling gene regulation with metabolic pathways. Proc Natl Acad Sci 116:3909–3918PubMedCrossRefGoogle Scholar
  144. Jiang L et al (2017) Quantitative metabolic flux analysis reveals an unconventional pathway of fatty acid synthesis in cancer cells deficient for the mitochondrial citrate transport protein. Metab Eng 43:198–207PubMedCrossRefGoogle Scholar
  145. Jiang J et al (2018) Asparagine, a critical limiting metabolite during glutamine starvation. Mol Cell Oncol 5:e1441633–e1441633PubMedPubMedCentralCrossRefGoogle Scholar
  146. Jin L, Zhou Y (2019) Crucial role of the pentose phosphate pathway in malignant tumors. Oncol Lett 17:4213–4221PubMedPubMedCentralGoogle Scholar
  147. José MM et al (2019) Metabolic reprogramming of cancer by chemicals that target glutaminase isoenzymes. Curr Med Chem 26:1–23CrossRefGoogle Scholar
  148. Kalinina EV et al (2014) Role of glutathione, glutathione transferase, and glutaredoxin in regulation of redox-dependent processes. Biochem Biokhimiia 79:1562–1583CrossRefGoogle Scholar
  149. Kang ES et al (2017) xCT deficiency aggravates acetaminophen-induced hepatotoxicity under inhibition of the transsulfuration pathway. Free Radic Res 51:80–90PubMedCrossRefGoogle Scholar
  150. Karagiannis GS et al (2012) Cancer-associated fibroblasts drive the progression of metastasis through both Paracrine and mechanical pressure on cancer tissue. Mol Cancer Res 10:1403–1418PubMedPubMedCentralCrossRefGoogle Scholar
  151. Kim YH et al (2013) Factors Affecting 18F-FDG uptake by metastatic lymph nodes in gastric cancer. J Comput Assist Tomogr 37:815–819PubMedCrossRefGoogle Scholar
  152. Kim YH et al (2017) SLC2A2 (GLUT2) as a novel prognostic factor for hepatocellular carcinoma. Oncotarget 8:68381–68392PubMedPubMedCentralGoogle Scholar
  153. Kitisin K et al (2011) Presentation and outcomes of hepatocellular carcinoma patients at a Western centre. HPB (Oxford) 13:712–722CrossRefGoogle Scholar
  154. Kleszcz R et al (2018) The inhibition of c-MYC transcription factor modulates the expression of glycolytic and glutaminolytic enzymes in FaDu hypopharyngeal carcinoma cells. Adv Clin Exp Med Off Organ Wroclaw Med Univ 27:735–742CrossRefGoogle Scholar
  155. Knudsen ES et al (2016) Unique metabolic features of pancreatic cancer stroma: relevance to the tumor compartment, prognosis, and invasive potential. Oncotarget 7:78396–78411PubMedPubMedCentralGoogle Scholar
  156. Ko Y-H et al (2011) Glutamine fuels a vicious cycle of autophagy in the tumor stroma and oxidative mitochondrial metabolism in epithelial cancer cells. Cancer Biol Ther 12:1085–1097PubMedPubMedCentralCrossRefGoogle Scholar
  157. Koh KX et al (2017) Acquired resistance to PI3K/mTOR inhibition is associated with mitochondrial DNA mutation and glycolysis. Oncotarget 8:110133–110144PubMedPubMedCentralGoogle Scholar
  158. Kolukula VK et al (2014) SLC25A1, or CIC, is a novel transcriptional target of mutant p53 and a negative tumor prognostic marker. Oncotarget 5:1212–1225PubMedPubMedCentralCrossRefGoogle Scholar
  159. Kong L et al (2016) Expression of lactate dehydrogenase C in MDAMB231 cells and its role in tumor invasion and migration. Mol Med Rep 13:3533–3538PubMedCrossRefGoogle Scholar
  160. Koochekpour S et al (2012) Serum glutamate levels correlate with Gleason score and glutamate blockade decreases proliferation, migration, and invasion and induces apoptosis in prostate cancer cells. Clin Cancer Res 18:5888–5901PubMedPubMedCentralCrossRefGoogle Scholar
  161. Koppula P et al (2017) The glutamate/cystine antiporter SLC7A11/xCT enhances cancer cell dependency on glucose by exporting glutamate. J Biol Chem 292:14240–14249PubMedPubMedCentralCrossRefGoogle Scholar
  162. Koprivica I et al (2019) Ethyl pyruvate stimulates regulatory T cells and ameliorates type 1 diabetes development in mice. Front Immunol 9:3130–3130PubMedPubMedCentralCrossRefGoogle Scholar
  163. Kowalik MA et al (2016) Metabolic reprogramming identifies the most aggressive lesions at early phases of hepatic carcinogenesis. Oncotarget 7:32375–32393PubMedPubMedCentralGoogle Scholar
  164. Kuo T-C et al (2016) Glutaminase 2 stabilizes dicer to repress snail and metastasis in hepatocellular carcinoma cells. Cancer Lett 383:282–294PubMedCrossRefGoogle Scholar
  165. Lally JSV et al (2019) Inhibition of acetyl-CoA carboxylase by phosphorylation or the inhibitor ND-654 suppresses lipogenesis and hepatocellular carcinoma. Cell Metab 29:174–182.e175PubMedCrossRefGoogle Scholar
  166. Lao-On U et al (2018) Roles of pyruvate carboxylase in human diseases: from diabetes to cancers and infection. J Mol Med 96:237–247PubMedCrossRefGoogle Scholar
  167. Le A et al (2012) Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells. Cell Metab 15:110–121PubMedPubMedCentralCrossRefGoogle Scholar
  168. Lee H-W et al (2013) Recruitment of monocytes/macrophages in different tumor microenvironments. Biochimica et Biophysica Acta (BBA) – Rev Cancer 1835:170–179CrossRefGoogle Scholar
  169. Lee J-H et al (2017) Stabilization of phosphofructokinase 1 platelet isoform by AKT promotes tumorigenesis. Nat Commun 8:949–949PubMedPubMedCentralCrossRefGoogle Scholar
  170. Lemire J et al (2008) Mitochondrial lactate dehydrogenase is involved in oxidative-energy metabolism in human astrocytoma cells (CCF-STTG1). PLoS One 3:e1550–e1550PubMedPubMedCentralCrossRefGoogle Scholar
  171. Li T, Le A (2018) Glutamine metabolism in cancer. In: Le A (ed) The heterogeneity of cancer metabolism. Springer, Cham, pp 13–32CrossRefGoogle Scholar
  172. Li H et al (2015) Cancer-associated fibroblasts provide a suitable microenvironment for tumor development and progression in oral tongue squamous cancer. J Transl Med 13:198PubMedPubMedCentralCrossRefGoogle Scholar
  173. Li S et al (2016) Inhibition of mTOR complex 2 induces GSK3/FBXW7-dependent degradation of sterol regulatory element-binding protein 1 (SREBP1) and suppresses lipogenesis in cancer cells. Oncogene 35:642–650PubMedCrossRefGoogle Scholar
  174. Li S et al (2018a) Acidic pHe regulates cytoskeletal dynamics through conformational integrin β1 activation and promotes membrane protrusion. Biochim Biophys Acta (BBA) – Mol Basis Dis 1864:2395–2408CrossRefGoogle Scholar
  175. Li Q et al (2018b) HSCs-derived COMP drives hepatocellular carcinoma progression by activating MEK/ERK and PI3K/AKT signaling pathways. J Exp Clin Cancer Res 37:231–231PubMedPubMedCentralCrossRefGoogle Scholar
  176. Li L et al (2019a) High developmental pluripotency-associated 4 expression promotes cell proliferation and glycolysis, and predicts poor prognosis in non-small-cell lung cancer. Mol Med Rep 20:445–454PubMedPubMedCentralGoogle Scholar
  177. Li J et al (2019b) miR-145 inhibits glutamine metabolism through c-myc/GLS1 pathways in ovarian cancer cells. Cell Biol Int 43:921–930PubMedCrossRefGoogle Scholar
  178. Li B et al (2019c) Targeting glutaminase 1 attenuates stemness properties in hepatocellular carcinoma by increasing reactive oxygen species and suppressing Wnt/beta-catenin pathway. EBioMedicine 39:239–254PubMedCrossRefGoogle Scholar
  179. Liang Y et al (2018) CD36 plays a critical role in proliferation, migration and tamoxifen-inhibited growth of ER-positive breast cancer cells. Oncogene 7:98–98CrossRefGoogle Scholar
  180. Lien EC et al (2016) Glutathione biosynthesis is a metabolic vulnerability in PI(3)K/Akt-driven breast cancer. Nat Cell Biol 18:572–578PubMedPubMedCentralCrossRefGoogle Scholar
  181. Lien EC et al (2017) Oncogenic PI3K promotes methionine dependency in breast cancer cells through the cystine-glutamate antiporter xCT. Sci Signal 10:eaao6604PubMedPubMedCentralCrossRefGoogle Scholar
  182. Lim JKM et al (2019) Cystine/glutamate antiporter xCT (SLC7A11) facilitates oncogenic RAS transformation by preserving intracellular redox balance. Proc Natl Acad Sci U S A 116:9433–9442PubMedPubMedCentralCrossRefGoogle Scholar
  183. Lin M-H, Miner JH (2015) Fatty acid transport protein 1 can compensate for fatty acid transport protein 4 in the developing mouse epidermis. J Invest Dermatol 135:462–470PubMedCrossRefGoogle Scholar
  184. Lin EY et al (2001) Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy. J Exp Med 193:727–740PubMedPubMedCentralCrossRefGoogle Scholar
  185. Lin R et al (2013) Acetylation stabilizes ATP-citrate lyase to promote lipid biosynthesis and tumor growth. Mol Cell 51:506–518PubMedPubMedCentralCrossRefGoogle Scholar
  186. Lin M et al (2018) Downregulation of CPT2 promotes tumorigenesis and chemoresistance to cisplatin in hepatocellular carcinoma. Onco Targets Ther 11:3101–3110PubMedPubMedCentralCrossRefGoogle Scholar
  187. Liu R-Z et al (2011) Association of FABP5 expression with poor survival in triple-negative breast cancer: implication for retinoic acid therapy. Am J Pathol 178:997–1008PubMedPubMedCentralCrossRefGoogle Scholar
  188. Liu F-L et al (2016) Autophagy is involved in TGF-β1-induced protective mechanisms and formation of cancer-associated fibroblasts phenotype in tumor microenvironment. Oncotarget 7:4122–4141PubMedGoogle Scholar
  189. Liu D et al (2017) Comprehensive proteomics analysis reveals metabolic reprogramming of tumor-associated macrophages stimulated by the tumor microenvironment. J Proteome Res 16:288–297PubMedCrossRefGoogle Scholar
  190. Liu M et al (2018) Tumor-suppressing effects of microRNA-612 in bladder cancer cells by targeting malic enzyme 1 expression. Int J Oncol 52:1923–1933PubMedPubMedCentralGoogle Scholar
  191. Liu J et al (2019) Peroxisomal regulation of redox homeostasis and adipocyte metabolism. Redox Biol 24:101167–101167PubMedPubMedCentralCrossRefGoogle Scholar
  192. Lo M et al (2008) The x cystine/glutamate antiporter: a potential target for therapy of cancer and other diseases. J Cell Physiol 215:593–602PubMedCrossRefGoogle Scholar
  193. Lomelino CL et al (2017) Asparagine synthetase: function, structure, and role in disease. J Biol Chem 292:19952–19958PubMedPubMedCentralCrossRefGoogle Scholar
  194. Lopes-Coelho F et al (2016) HNF1β drives glutathione (GSH) synthesis underlying intrinsic carboplatin resistance of ovarian clear cell carcinoma (OCCC). Tumor Biol 37:4813–4829CrossRefGoogle Scholar
  195. Lopes-Coelho F et al (2017) Monocarboxylate transporter 1 (MCT1), a tool to stratify acute myeloid leukemia (AML) patients and a vehicle to kill cancer cells. Oncotarget 8:82803–82823PubMedPubMedCentralCrossRefGoogle Scholar
  196. Lopes-Coelho F et al (2018) Breast cancer metabolic cross-talk: fibroblasts are hubs and breast cancer cells are gatherers of lipids. Mol Cell Endocrinol 462:93–106CrossRefGoogle Scholar
  197. Lu Y-X et al (2018) ME1 regulates NADPH homeostasis to promote gastric cancer growth and metastasis. Cancer Res 78:1972–1985PubMedCrossRefGoogle Scholar
  198. Lu X et al (2019) Metabolic profiling analysis upon acylcarnitines in tissues of hepatocellular carcinoma revealed the inhibited carnitine shuttle system caused by the downregulated carnitine palmitoyltransferase 2. Mol Carcinog 58:749–759PubMedCrossRefGoogle Scholar
  199. Luebker SA, Koepsell SA (2019) Diverse mechanisms of BRAF inhibitor resistance in melanoma identified in clinical and preclinical studies. Front Oncol 9:268–268PubMedPubMedCentralCrossRefGoogle Scholar
  200. Lukey MJ et al (2013) Therapeutic strategies impacting cancer cell glutamine metabolism. Future Med Chem 5:1685–1700PubMedPubMedCentralCrossRefGoogle Scholar
  201. Luo W et al (2011) Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. Cell 145:732–744PubMedPubMedCentralCrossRefGoogle Scholar
  202. Lv Q et al (2019) FABP5 regulates the proliferation of clear cell renal cell carcinoma cells via the PI3K/AKT signaling pathway. Int J Oncol 54:1221–1232PubMedPubMedCentralGoogle Scholar
  203. Lyssiotis CA, Cantley LC (2014) Acetate fuels the cancer engine. Cell 159:1492–1494PubMedCrossRefGoogle Scholar
  204. Mackenzie R et al (2015) Targeted deep sequencing of mucinous ovarian tumors reveals multiple overlapping RAS-pathway activating mutations in borderline and cancerous neoplasms. BMC Cancer 15:415–415PubMedPubMedCentralCrossRefGoogle Scholar
  205. Madunić IV et al (2018) Sodium-glucose cotransporters: new targets of cancer therapy? Arhiv za higijenu rada i toksikologiju 69:278PubMedCrossRefGoogle Scholar
  206. Manabe Y et al (2003) Mature adipocytes, but not preadipocytes, promote the growth of breast carcinoma cells in collagen gel matrix culture through cancer–stromal cell interactions. J Pathol 201:221–228CrossRefGoogle Scholar
  207. Mantovani A, Sica A (2010) Macrophages, innate immunity and cancer: balance, tolerance, and diversity. Curr Opin Immunol 22:231–237PubMedCrossRefGoogle Scholar
  208. Mantovani A et al (2006) Role of tumor-associated macrophages in tumor progression and invasion. Cancer Metastasis Rev 25:315–322PubMedCrossRefGoogle Scholar
  209. Mao Y et al (2013) Stromal cells in tumor microenvironment and breast cancer. Cancer Metastasis Rev 32:303–315PubMedPubMedCentralCrossRefGoogle Scholar
  210. Mao A et al (2019) KLF8 is associated with poor prognosis and regulates glycolysis by targeting GLUT4 in gastric cancer. J Cell Mol Med 23:5087–5097PubMedPubMedCentralCrossRefGoogle Scholar
  211. Marani M et al (2016) A pyrazolopyran derivative preferentially inhibits the activity of human cytosolic serine hydroxymethyltransferase and induces cell death in lung cancer cells. Oncotarget 7:4570–4583PubMedCrossRefGoogle Scholar
  212. Marchiq I, Pouysségur J (2016) Hypoxia, cancer metabolism and the therapeutic benefit of targeting lactate/H+ symporters. J Mol Med 94:155–171PubMedCrossRefGoogle Scholar
  213. Marino SM, Gladyshev VN (2012) Analysis and functional prediction of reactive cysteine residues. J Biol Chem 287:4419–4425PubMedCrossRefGoogle Scholar
  214. Martinez-Outschoorn UE et al (2010) Autophagy in cancer associated fibroblasts promotes tumor cell survival. Cell Cycle 9:3515–3533PubMedPubMedCentralCrossRefGoogle Scholar
  215. Martinez-Outschoorn UE et al (2011) Cancer cells metabolically “fertilize” the tumor microenvironment with hydrogen peroxide, driving the Warburg effect. Cell Cycle 10:2504–2520PubMedPubMedCentralCrossRefGoogle Scholar
  216. Martinez-Outschoorn UE et al (2014) Catabolic cancer-associated fibroblasts transfer energy and biomass to anabolic cancer cells, fueling tumor growth. Semin Cancer Biol 25:47–60PubMedCrossRefGoogle Scholar
  217. Mashek DG et al (2004) Revised nomenclature for the mammalian long-chain acyl-CoA synthetase gene family. J Lipid Res 45:1958–1961PubMedCrossRefGoogle Scholar
  218. Mashima T et al (2009) Acyl-CoA synthetase as a cancer survival factor: its inhibition enhances the efficacy of etoposide. Cancer Sci 100:1556–1562PubMedCrossRefGoogle Scholar
  219. Mashimo T et al (2014) Acetate is a bioenergetic substrate for human glioblastoma and brain metastases. Cell 159:1603–1614PubMedPubMedCentralCrossRefGoogle Scholar
  220. Mates JM et al (2013) Glutaminase isoenzymes as key regulators in metabolic and oxidative stress against cancer. Curr Mol Med 13:514–534PubMedCrossRefGoogle Scholar
  221. Matés JM et al (2018) Glutaminase isoenzymes in the metabolic therapy of cancer. Biochimica et Biophysica Acta (BBA) – Rev Cancer 1870:158–164CrossRefGoogle Scholar
  222. Mathupala SP et al (2009) Hexokinase-2 bound to mitochondria: cancer’s stygian link to the “Warburg effect” and a pivotal target for effective therapy. Semin Cancer Biol 19:17–24PubMedCrossRefGoogle Scholar
  223. McBrian MA et al (2013) Histone acetylation regulates intracellular pH. Mol Cell 49:310–321PubMedCrossRefGoogle Scholar
  224. Mele L et al (2019) Glucose-6-phosphate dehydrogenase blockade potentiates tyrosine kinase inhibitor effect on breast cancer cells through autophagy perturbation. J Exp Clin Cancer Res 38:160–160PubMedPubMedCentralCrossRefGoogle Scholar
  225. Menard JA et al (2016) Metastasis stimulation by hypoxia and acidosis-induced extracellular lipid uptake is mediated by proteoglycan-dependent endocytosis. Cancer Res 76:4828–4840CrossRefGoogle Scholar
  226. Menendez JA, Lupu R (2007) Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat Rev Cancer 7:763PubMedCrossRefGoogle Scholar
  227. Menendez JA et al (2016) The metastasis inducer CCN1 (CYR61) activates the fatty acid synthase (FASN)-driven lipogenic phenotype in breast cancer cells. Oncoscience 3:242–257PubMedPubMedCentralGoogle Scholar
  228. Metallo CM et al (2011) Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature 481:380–384PubMedPubMedCentralCrossRefGoogle Scholar
  229. Mieyal JJ et al (2008) Molecular mechanisms and clinical implications of reversible protein S-glutathionylation. Antioxid Redox Signal 10:1941–1988PubMedPubMedCentralCrossRefGoogle Scholar
  230. Milger K et al (2006) Cellular uptake of fatty acids driven by the ER-localized acyl-CoA synthetase FATP4. J Cell Sci 119:4678–4688PubMedCrossRefGoogle Scholar
  231. Módis K et al (2013) Hydrogen sulfide-mediated stimulation of mitochondrial electron transport involves inhibition of the mitochondrial phosphodiesterase 2A, elevation of cAMP and activation of protein kinase A. Biochem Pharmacol 86:1311–1319PubMedCrossRefGoogle Scholar
  232. Moellering RE et al (2008) Acid treatment of melanoma cells selects for invasive phenotypes. Clin Exp Metastasis 25:411–425PubMedCrossRefGoogle Scholar
  233. Monroe GR et al (2019) Identification of human D lactate dehydrogenase deficiency. Nat Commun 10:1477–1477PubMedPubMedCentralCrossRefGoogle Scholar
  234. Moon J-S et al (2011) Krüppel-like factor 4 (KLF4) activates the transcription of the gene for the platelet isoform of phosphofructokinase (PFKP) in breast cancer. J Biol Chem 286:23808–23816PubMedPubMedCentralCrossRefGoogle Scholar
  235. Mossmann D et al (2018) mTOR signalling and cellular metabolism are mutual determinants in cancer. Nat Rev Cancer 18:744–757PubMedCrossRefGoogle Scholar
  236. Mroczko B et al (2007) Serum macrophage-colony stimulating factor levels in colorectal cancer patients correlate with lymph node metastasis and poor prognosis. Clin Chim Acta 380:208–212PubMedCrossRefPubMedCentralGoogle Scholar
  237. Munir R et al (2019) Lipid metabolism in cancer cells under metabolic stress. Br J Cancer 120:1090–1098CrossRefGoogle Scholar
  238. Nagao K et al (2018) Fatty acid binding protein 7 may be a marker and therapeutic targets in clear cell renal cell carcinoma. BMC Cancer 18:1114–1114PubMedPubMedCentralCrossRefGoogle Scholar
  239. Nakashima C et al (2018) Expression of cytosolic malic enzyme (ME1) is associated with disease progression in human oral squamous cell carcinoma. Cancer Sci 109:2036–2045PubMedPubMedCentralCrossRefGoogle Scholar
  240. Netto LES et al (2007) Reactive cysteine in proteins: protein folding, antioxidant defense, redox signaling and more. Comp Biochem Physiol Part C Toxicol Pharmacol 146:180–193CrossRefGoogle Scholar
  241. Nguyen XC et al (2008) High correlations between primary tumours and loco-regional metastatic lymph nodes in non-small-cell lung cancer with respect to glucose transporter type 1-mediated 2-deoxy-2-F18-fluoro-d-glucose uptake. Eur J Cancer 44:692–698PubMedCrossRefGoogle Scholar
  242. Nieman KM et al (2011) Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nat Med 17:1498–1503PubMedPubMedCentralCrossRefGoogle Scholar
  243. Nunes SC, Serpa J (2018) Glutathione in ovarian cancer: a double-edged sword. Int J Mol Sci 19:1882PubMedCentralCrossRefPubMedGoogle Scholar
  244. Nunes SC et al (2018a) Cysteine boosters the evolutionary adaptation to CoCl(2) mimicked hypoxia conditions, favouring carboplatin resistance in ovarian cancer. BMC Evol Biol 18:97–97PubMedPubMedCentralCrossRefGoogle Scholar
  245. Nunes SC et al (2018b) Cysteine allows ovarian cancer cells to adapt to hypoxia and to escape from carboplatin cytotoxicity. Sci Rep 8:9513–9513PubMedPubMedCentralCrossRefGoogle Scholar
  246. Okuno S et al (2003) Role of cystine transport in intracellular glutathione level and cisplatin resistance in human ovarian cancer cell lines. Br J Cancer 88:951–956PubMedPubMedCentralCrossRefGoogle Scholar
  247. Orimo A, Weinberg RA (2006) Stromal fibroblasts in cancer: a novel tumor-promoting cell type. Cell Cycle 5:1597–1601PubMedCrossRefGoogle Scholar
  248. Pan Y et al (2015) Radiation exposure promotes hepatocarcinoma cell invasion through epithelial mesenchymal transition mediated by H<sub>2</sub>S/CSE pathway. Radiat Res 185(96–105):110Google Scholar
  249. Pan J et al (2019) CD36 mediates palmitate acid-induced metastasis of gastric cancer via AKT/GSK-3β/β-catenin pathway. J Exp Clin Cancer Res 38:52–52PubMedPubMedCentralCrossRefGoogle Scholar
  250. Panza E et al (2015) Role of the cystathionine γ lyase/hydrogen sulfide pathway in human melanoma progression. Pigment Cell Melanoma Res 28:61–72PubMedCrossRefGoogle Scholar
  251. Paradise RK et al (2011) Acidic extracellular pH promotes activation of integrin α(v)β(3). PLoS One 6:e15746–e15746PubMedPubMedCentralCrossRefGoogle Scholar
  252. Park Y-Y et al (2013) Tat-activating regulatory DNA-binding protein regulates glycolysis in hepatocellular carcinoma by regulating the platelet isoform of phosphofructokinase through microRNA 520. Hepatology 58:182–191PubMedPubMedCentralCrossRefGoogle Scholar
  253. Patra KC, Hay N (2014) The pentose phosphate pathway and cancer. Trends Biochem Sci 39:347–354PubMedPubMedCentralCrossRefGoogle Scholar
  254. Pattanayak SP et al (2018) Bergapten inhibits liver carcinogenesis by modulating LXR/PI3K/Akt and IDOL/LDLR pathways. Biomed Pharmacother 108:297–308PubMedCrossRefGoogle Scholar
  255. Pavlides S et al (2009) The reverse Warburg effect: aerobic glycolysis in cancer associated fibroblasts and the tumor stroma. Cell Cycle 8:3984–4001CrossRefGoogle Scholar
  256. Pavlova NN, Thompson CB (2016) The emerging hallmarks of cancer metabolism. Cell Metab 23:27–47PubMedPubMedCentralCrossRefGoogle Scholar
  257. Pedraz-Cuesta E et al (2015) The glutamate transport inhibitor DL-Threo-β-Benzyloxyaspartic acid (DL-TBOA) differentially affects SN38- and oxaliplatin-induced death of drug-resistant colorectal cancer cells. BMC Cancer 15:411–411PubMedPubMedCentralCrossRefGoogle Scholar
  258. Penny HL et al (2016) Warburg metabolism in tumor-conditioned macrophages promotes metastasis in human pancreatic ductal adenocarcinoma. Oncoimmunology 5:e1191731–e1191731PubMedPubMedCentralCrossRefGoogle Scholar
  259. Pérez-Miguelsanz J et al (2017) Betaine homocysteine S-methyltransferase emerges as a new player of the nuclear methionine cycle. Biochimica et Biophysica Acta (BBA) – Mol Cell Res 1864:1165–1182CrossRefGoogle Scholar
  260. Pértega-Gomes N et al (2014) A lactate shuttle system between tumour and stromal cells is associated with poor prognosis in prostate cancer. BMC Cancer 14:352PubMedPubMedCentralCrossRefGoogle Scholar
  261. Picon-Ruiz M et al (2016) Interactions between adipocytes and breast cancer cells stimulate cytokine production and drive Src/Sox2/miR-302b–mediated malignant progression. Cancer Res 76:491–504CrossRefGoogle Scholar
  262. Pissimissis N et al (2009) The Glutamatergic system expression in human PC-3 and LNCaP prostate cancer cells. Anticancer Res 29:371–377PubMedGoogle Scholar
  263. Poisson LM et al (2015) A metabolomic approach to identifying platinum resistance in ovarian cancer. J Ovarian Res 8:13–13PubMedPubMedCentralCrossRefGoogle Scholar
  264. Pollard JW (2009) Trophic macrophages in development and disease. Nat Rev Immunol 9:259–270PubMedPubMedCentralCrossRefGoogle Scholar
  265. Porstmann T et al (2008) SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth. Cell Metab 8:224–236PubMedPubMedCentralCrossRefGoogle Scholar
  266. Potts A et al (2018) Cytosolic phosphoenolpyruvate carboxykinase as a cataplerotic pathway in the small intestine. Am J Physiol Gastrointest Liver Physiol 315:G249–G258PubMedPubMedCentralCrossRefGoogle Scholar
  267. Qiao A et al (2016) Breast cancer-associated fibroblasts: their roles in tumor initiation, progression and clinical applications. Front Med 10:33–40PubMedCrossRefGoogle Scholar
  268. Rajasinghe LD et al (2019) Delta-tocotrienol modulates glutamine dependence by inhibiting ASCT2 and LAT1 transporters in non-small cell lung cancer (NSCLC) cells: a metabolomic approach. Metabolites 9:50PubMedCentralCrossRefPubMedGoogle Scholar
  269. Ramapriyan R et al (2019) Altered cancer metabolism in mechanisms of immunotherapy resistance. Pharmacol Ther 195:162–171PubMedCrossRefGoogle Scholar
  270. Ramos-Martinez JI (2017) The regulation of the pentose phosphate pathway: remember Krebs. Arch Biochem Biophys 614:50–52PubMedCrossRefGoogle Scholar
  271. Read JA et al (2001) Structural basis for altered activity of M- and H-isozyme forms of human lactate dehydrogenase. Proteins 43:175–185PubMedCrossRefGoogle Scholar
  272. Reis LMD et al (2019) Dual inhibition of glutaminase and carnitine palmitoyltransferase decreases growth and migration of glutaminase inhibition–resistant triple-negative breast cancer cells. J Biol Chem 294:9342–9357PubMedCrossRefGoogle Scholar
  273. Reynolds MR et al (2013) Control of glutamine metabolism by the tumor suppressor Rb. Oncogene 33:556PubMedPubMedCentralCrossRefGoogle Scholar
  274. Reynolds MR et al (2014) Control of glutamine metabolism by the tumor suppressor Rb. Oncogene 33:556–566PubMedCrossRefGoogle Scholar
  275. Ricci M et al (2018) PPARs are mediators of anti-cancer properties of superparamagnetic iron oxide nanoparticles (SPIONs) functionalized with conjugated linoleic acid. Chem Biol Interact 292:9–14PubMedCrossRefGoogle Scholar
  276. Riganti C et al (2012) The pentose phosphate pathway: an antioxidant defense and a crossroad in tumor cell fate. Free Radic Biol Med 53:421–436PubMedCrossRefGoogle Scholar
  277. Rodríguez-Enríquez S et al (2000) Substrate oxidation and ATP supply in AS-30D hepatoma cells. Arch Biochem Biophys 375:21–30PubMedCrossRefPubMedCentralGoogle Scholar
  278. Rodríguez-Enríquez S et al (2006) Control of cellular proliferation by modulation of oxidative phosphorylation in human and rodent fast-growing tumor cells. Toxicol Appl Pharmacol 215:208–217PubMedCrossRefPubMedCentralGoogle Scholar
  279. Rohani N et al (2019) Acidification of tumor at stromal boundaries drives transcriptome alterations associated with aggressive phenotypes. Cancer Res 79:1952–1966PubMedCrossRefGoogle Scholar
  280. Romero R et al (2017) Keap1 loss promotes Kras-driven lung cancer and results in dependence on glutaminolysis. Nat Med 23:1362–1368PubMedPubMedCentralCrossRefGoogle Scholar
  281. Rozovski U et al (2018) STAT3-activated CD36 facilitates fatty acid uptake in chronic lymphocytic leukemia cells. Oncotarget 9:21268–21280PubMedPubMedCentralGoogle Scholar
  282. Rudolph MC et al (2012) Mammalian fatty acid synthase activity from crude tissue lysates tracing 13C-labeled substrates using gas chromatography-mass spectrometry. Anal Biochem 428:158–166PubMedPubMedCentralCrossRefGoogle Scholar
  283. Saha SK et al (2019) Multiomics analysis reveals that GLS and GLS2 differentially modulate the clinical outcomes of cancer. J Clin Med 8:355PubMedCentralCrossRefPubMedGoogle Scholar
  284. Sanità P et al (2014) Tumor-stroma metabolic relationship based on lactate shuttle can sustain prostate cancer progression. BMC Cancer 14:154–154PubMedPubMedCentralCrossRefGoogle Scholar
  285. Santander AM et al (2015) Paracrine interactions between adipocytes and tumor cells recruit and modify macrophages to the mammary tumor microenvironment: the role of Obesity and inflammation in breast adipose tissue. Cancers (Basel) 7:143–178CrossRefGoogle Scholar
  286. Santi A et al (2013) The effects of CA IX catalysis products within tumor microenvironment. Cell Commun Signal 11:81–81PubMedPubMedCentralCrossRefGoogle Scholar
  287. Sarfraz I et al (2018) Malic enzyme 2 as a potential therapeutic drug target for cancer. IUBMB Life 70:1076–1083PubMedCrossRefGoogle Scholar
  288. Sato-Tadano A et al (2013) Hexokinase II in breast carcinoma: a potent prognostic factor associated with hypoxia-inducible factor-1α and Ki-67. Cancer Sci 104:1380–1388PubMedCrossRefGoogle Scholar
  289. Sawayama H et al (2019) Glucose transporter 1 regulates the proliferation and cisplatin sensitivity of esophageal cancer. Cancer Sci 110:1705–1714PubMedPubMedCentralCrossRefGoogle Scholar
  290. Scheepers A et al (2004) The glucose transporter families SGLT and GLUT: molecular basis of normal and aberrant function. J Parenter Enter Nutr 28:364–371CrossRefGoogle Scholar
  291. Sekiguchi F et al (2016) Endogenous hydrogen sulfide enhances cell proliferation of human gastric cancer AGS cells. Biol Pharm Bull 39:887–890PubMedCrossRefGoogle Scholar
  292. Selvarajah B et al (2019) mTORC1 amplifies the ATF4-dependent de novo serine-glycine pathway to supply glycine during TGF-β<sub>1</sub>–induced collagen biosynthesis. Sci Signal 12:eaav3048PubMedPubMedCentralCrossRefGoogle Scholar
  293. Sen S et al (2015) Role of cystathionine β-synthase in human breast Cancer. Free Radic Biol Med 86:228–238PubMedCrossRefGoogle Scholar
  294. Shiozaki A et al (2014) xCT, component of cysteine/glutamate transporter, as an independent prognostic factor in human esophageal squamous cell carcinoma. J Gastroenterol 49:853–863PubMedCrossRefGoogle Scholar
  295. Shpilberg Y et al (2015) The direct and indirect effects of corticosterone and primary adipose tissue on MCF7 breast cancer cell cycle progression. In: Hormone molecular Biology and clinical investigation. De Gruyter, Berlin, p 91Google Scholar
  296. Sikder MOF et al (2017) The Na+/Cl−-coupled, broad-specific, amino acid transporter SLC6A14 (ATB0,+): emerging roles in multiple diseases and therapeutic potential for treatment and diagnosis. AAPS J 20:12PubMedCrossRefGoogle Scholar
  297. Silva LS et al (2016) STAT3:FOXM1 and MCT1 drive uterine cervix carcinoma fitness to a lactate-rich microenvironment. Tumor Biol 37:5385–5395CrossRefGoogle Scholar
  298. Singh R, Cuervo AM (2012) Lipophagy: connecting autophagy and lipid metabolism. Int J Cell Biol 2012:282041–282041PubMedPubMedCentralCrossRefGoogle Scholar
  299. Singh R et al (2009) Autophagy regulates lipid metabolism. Nature 458:1131–1135PubMedPubMedCentralCrossRefGoogle Scholar
  300. Son J et al (2013) Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature 496:101–105PubMedPubMedCentralCrossRefGoogle Scholar
  301. Stahl A et al (2002) Insulin causes fatty acid transport Protein translocation and enhanced fatty Acid uptake in adipocytes. Dev Cell 2:477–488PubMedCrossRefGoogle Scholar
  302. Stepulak A et al (2014) Glutamate and its receptors in cancer. J Neural Transm (Vienna) 121:933–944CrossRefGoogle Scholar
  303. Still ER, Yuneva MO (2017) Hopefully devoted to Q: targeting glutamine addiction in cancer. Br J Cancer 116:1375–1381PubMedPubMedCentralCrossRefGoogle Scholar
  304. Stincone A et al (2015) The return of metabolism: biochemistry and physiology of the pentose phosphate pathway. Biol Rev Camb Philos Soc 90:927–963PubMedCrossRefGoogle Scholar
  305. Storch J, McDermott L (2009) Structural and functional analysis of fatty acid-binding proteins. J Lipid Res 50(Suppl):S126–S131PubMedPubMedCentralCrossRefGoogle Scholar
  306. Su Y et al (2013) Id1 enhances human ovarian cancer endothelial progenitor cell angiogenesis via PI3K/Akt and NF-κB/MMP-2 signaling pathways. J Transl Med 11:132–132PubMedPubMedCentralCrossRefGoogle Scholar
  307. Sun L et al (2017) Decreased expression of acetyl-CoA synthase 2 promotes metastasis and predicts poor prognosis in hepatocellular carcinoma. Cancer Sci 108:1338–1346PubMedPubMedCentralCrossRefGoogle Scholar
  308. Sun Q et al (2018) Hypermethylated CD36 gene affected the progression of lung cancer. Gene 678:395–406PubMedCrossRefGoogle Scholar
  309. Sun T et al (2019) Anoikis resistant mediated by FASN promoted growth and metastasis of osteosarcoma. Cell Death Dis 10:298–298PubMedPubMedCentralCrossRefGoogle Scholar
  310. Sung YK et al (2007) Regulation of cell growth by fatty acid-CoA ligase 4 in human hepatocellular carcinoma cells. Exp Amp Mol Med 39:477CrossRefGoogle Scholar
  311. Suzuki S et al (2010) Phosphate-activated glutaminase (GLS2), a p53-inducible regulator of glutamine metabolism and reactive oxygen species. Proc Natl Acad Sci U S A 107:7461–7466PubMedPubMedCentralCrossRefGoogle Scholar
  312. Swierczynski J et al (2014) Role of abnormal lipid metabolism in development, progression, diagnosis and therapy of pancreatic cancer. World J Gastroenterol 20:2279–2303PubMedPubMedCentralCrossRefGoogle Scholar
  313. Szabo C et al (2013) Tumor-derived hydrogen sulfide, produced by cystathionine-β-synthase, stimulates bioenergetics, cell proliferation, and angiogenesis in colon cancer. Proc Natl Acad Sci U S A 110:12474–12479PubMedPubMedCentralCrossRefGoogle Scholar
  314. Tang H, Goldberg E (2009) Homo sapiens Lactate Dehydrogenase c (Ldhc) gene expression in cancer cells is regulated by transcription factor Sp1, CREB, and CpG island methylation. J Androl 30:157–167PubMedCrossRefGoogle Scholar
  315. Tannahill GM et al (2013) Succinate is an inflammatory signal that induces IL-1β through HIF-1α. Nature 496:238–242PubMedPubMedCentralCrossRefGoogle Scholar
  316. Tchou J et al (2012) Human breast cancer associated fibroblasts exhibit subtype specific gene expression profiles. BMC Med Genet 5:39Google Scholar
  317. Thangaraju M et al (2006) SLC5A8 triggers tumor cell apoptosis through pyruvate-dependent inhibition of histone deacetylases. Cancer Res 66:11560–11564PubMedCrossRefGoogle Scholar
  318. Thoen LFR et al (2011) A role for autophagy during hepatic stellate cell activation. J Hepatol 55:1353–1360PubMedCrossRefGoogle Scholar
  319. Tisdale MJ (2002) Cachexia in cancer patients. Nat Rev Cancer 2:862–871PubMedCrossRefGoogle Scholar
  320. Toy EP et al (2009) Enhanced ovarian cancer tumorigenesis and metastasis by the macrophage colony-stimulating factor. Neoplasia (New York NY) 11:136–144CrossRefGoogle Scholar
  321. Traverso N et al (2013) Role of glutathione in cancer progression and chemoresistance. Oxidative Med Cell Longev 2013:972913–972913CrossRefGoogle Scholar
  322. Tsai W-W et al (2015) ATF3 mediates inhibitory effects of ethanol on hepatic gluconeogenesis. Proc Natl Acad Sci U S A 112:2699–2704PubMedPubMedCentralCrossRefGoogle Scholar
  323. Turbat-Herrera EA et al (2018) Cystathione β-synthase is increased in thyroid malignancies. Anticancer Res 38:6085–6090PubMedCrossRefGoogle Scholar
  324. Ueno T et al (2000) Significance of macrophage chemoattractant protein-1 in macrophage recruitment, angiogenesis, and survival in human breast cancer. Clin Cancer Res 6:3282–3289PubMedPubMedCentralGoogle Scholar
  325. Umapathy A et al (2018) Functional characterisation of glutathione export from the rat lens. Exp Eye Res 166:151–159PubMedCrossRefGoogle Scholar
  326. Updegraff BL et al (2018) Transmembrane protease TMPRSS11B promotes lung cancer growth by enhancing lactate export and glycolytic metabolism. Cell Rep 25:2223–2233.e2226PubMedPubMedCentralCrossRefGoogle Scholar
  327. Valsecchi R et al (2016) HIF-1α regulates the interaction of chronic lymphocytic leukemia cells with the tumor microenvironment. Blood 127:1987–1997PubMedPubMedCentralCrossRefGoogle Scholar
  328. Valvona CJ et al (2016) The regulation and function of lactate dehydrogenase A: therapeutic potential in brain tumor. Brain Pathol 26:3–17PubMedCrossRefGoogle Scholar
  329. van Jaarsveld MTM et al (2015) miR-634 restores drug sensitivity in resistant ovarian cancer cells by targeting the Ras-MAPK pathway. Mol Cancer 14:196–196PubMedPubMedCentralCrossRefGoogle Scholar
  330. Vangapandu HV et al (2017) The Stromal microenvironment modulates mitochondrial oxidative phosphorylation in chronic Lymphocytic leukemia cells. Neoplasia 19:762–771PubMedPubMedCentralCrossRefGoogle Scholar
  331. Vanhove K et al (2019) Glutamine addiction and therapeutic strategies in lung cancer. Int J Mol Sci 20:252PubMedCentralCrossRefPubMedGoogle Scholar
  332. Viale A, Corti D, Draetta GF (2015) Highlights from recent cancer literature. Cancer Res 75:3685–3686PubMedCrossRefGoogle Scholar
  333. Visscher M et al (2016) Covalent targeting of acquired cysteines in cancer. Curr Opin Chem Biol 30:61–67PubMedCrossRefGoogle Scholar
  334. Wahi K, Holst J (2019) ASCT2: a potential cancer drug target. Expert Opin Ther Targets 23:555–558PubMedCrossRefGoogle Scholar
  335. Wang R (2012) Physiological implications of hydrogen sulfide: a whiff exploration that blossomed. Physiol Rev 92:791–896PubMedCrossRefGoogle Scholar
  336. Wang W, Ballatori N (1998) Endogenous glutathione conjugates: occurrence and biological functions. Pharmacol Rev 50:335–356PubMedGoogle Scholar
  337. Wang Z, Dong C (2019) Gluconeogenesis in cancer: function and regulation of PEPCK, FBPase, and G6Pase. Trends Cancer 5:30–45PubMedCrossRefGoogle Scholar
  338. Wang Y et al (2012a) Prognostic and therapeutic implications of increased ATP citrate lyase expression in human epithelial ovarian cancer. Oncol Rep 27:1156–1162PubMedPubMedCentralCrossRefGoogle Scholar
  339. Wang Y-Y et al (2012b) Adipose tissue and breast epithelial cells: a dangerous dynamic duo in breast cancer. Cancer Lett 324:142–151PubMedCrossRefGoogle Scholar
  340. Wang Q et al (2014a) Targeting glutamine transport to suppress melanoma cell growth. Int J Cancer 135:1060–1071PubMedCrossRefGoogle Scholar
  341. Wang F et al (2014b) Mammary fat of breast cancer: gene expression profiling and functional characterization. PLoS One 9:e109742–e109742PubMedPubMedCentralCrossRefGoogle Scholar
  342. Wang C et al (2015) Human adipocytes stimulate invasion of breast cancer MCF-7 cells by secreting IGFBP-2. PLoS One 10:e0119348–e0119348PubMedPubMedCentralCrossRefGoogle Scholar
  343. Wang Q et al (2016) Autophagy protects ovarian cancer-associated fibroblasts against oxidative stress. Cell Cycle 15:1376–1385PubMedPubMedCentralCrossRefGoogle Scholar
  344. Wang H et al (2017a) The metabolic function of cyclin D3-CDK6 kinase in cancer cell survival. Nature 546:426–430PubMedPubMedCentralCrossRefGoogle Scholar
  345. Wang M et al (2017b) Uncoupling protein 2 downregulation by hypoxia through repression of peroxisome proliferator-activated receptor γ promotes chemoresistance of non-small cell lung cancer. Oncotarget 8:8083–8094PubMedGoogle Scholar
  346. Wang YY et al (2017c) Mammary adipocytes stimulate breast cancer invasion through metabolic remodeling of tumor cells. JCI Insight 2:e87489–e87489PubMedPubMedCentralGoogle Scholar
  347. Wang S et al (2018a) KRAB-type zinc-finger proteins PITA and PISA specifically regulate p53-dependent glycolysis and mitochondrial respiration. Cell Res 28:572–592PubMedPubMedCentralCrossRefGoogle Scholar
  348. Wang Y et al (2018b) Prognostic value of D-lactate dehydrogenase in patients with clear cell renal cell carcinoma. Oncol Lett 16:866–874PubMedPubMedCentralGoogle Scholar
  349. Wang L et al (2019a) Wnt1-inducible signaling protein 1 regulates laryngeal squamous cell carcinoma glycolysis and chemoresistance via the YAP1/TEAD1/GLUT1 pathway. J Cell Physiol 234:15941–15950CrossRefGoogle Scholar
  350. Wang X et al (2019b) Nf1 loss promotes Kras-driven lung adenocarcinoma and results in Psat1-mediated glutamate dependence. EMBO Mol Med 11:e9856PubMedPubMedCentralCrossRefGoogle Scholar
  351. Wang L et al (2019c) I157172, a novel inhibitor of cystathionine gamma-lyase, inhibits growth and migration of breast cancer cells via SIRT1-mediated deacetylation of STAT3. Oncol Rep 41:427–436PubMedGoogle Scholar
  352. Wang Y et al (2019d) Inhibition of fatty acid synthesis arrests colorectal neoplasm growth and metastasis: anti-cancer therapeutical effects of natural cyclopeptide RA-XII. Biochem Biophys Res Commun 512:819–824PubMedCrossRefGoogle Scholar
  353. Warburg O (1956) On the origin of cancer cells. Science 123:309–314CrossRefGoogle Scholar
  354. Weber GF (2016) Metabolism in cancer metastasis. Int J Cancer 138:2061–2066PubMedCrossRefGoogle Scholar
  355. Wei L et al (2016) Leptin promotes epithelial-mesenchymal transition of breast cancer via the upregulation of pyruvate kinase M2. J Exp Clin Cancer Res 35:166–166PubMedPubMedCentralCrossRefGoogle Scholar
  356. Wei J et al (2019) An allosteric mechanism for potent inhibition of human ATP-citrate lyase. Nature 568:566–570PubMedCrossRefGoogle Scholar
  357. Wellen KE et al (2009) ATP-citrate lyase links cellular metabolism to histone acetylation. Science 324:1076–1080PubMedPubMedCentralCrossRefGoogle Scholar
  358. Wen Y-A et al (2017) Adipocytes activate mitochondrial fatty acid oxidation and autophagy to promote tumor growth in colon cancer. Cell Death Dis 8:e2593–e2593PubMedPubMedCentralCrossRefGoogle Scholar
  359. Wen H et al (2019) Glucose-derived acetate and ACSS2 as key players in cisplatin resistance in bladder cancer. Biochimica et Biophysica Acta (BBA) – Mol Cell Biol Lipids 1864:413–421CrossRefGoogle Scholar
  360. Wenes M et al (2016) Macrophage metabolism controls tumor blood vessel morphogenesis and metastasis. Cell Metab 24:701–715PubMedCrossRefGoogle Scholar
  361. Wise DR, Thompson CB (2010) Glutamine addiction: a new therapeutic target in cancer. Trends Biochem Sci 35:427–433PubMedPubMedCentralCrossRefGoogle Scholar
  362. Wise DR 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
  363. Wise DR et al (2011) Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of α-ketoglutarate to citrate to support cell growth and viability. Proc Natl Acad Sci U S A 108:19611–19616PubMedPubMedCentralCrossRefGoogle Scholar
  364. Witz IP (2009) The tumor microenvironment: the making of a paradigm. Cancer Microenviron 2(Suppl 1):9–17PubMedPubMedCentralCrossRefGoogle Scholar
  365. Wu G et al (2004) Glutathione metabolism and its implications for health. J Nutr 134:489–492PubMedPubMedCentralCrossRefGoogle Scholar
  366. Wu Q et al (2006) FATP1 is an insulin-sensitive fatty acid transporter involved in diet-induced obesity. Mol Cell Biol 26:3455–3467PubMedPubMedCentralCrossRefGoogle Scholar
  367. Wu R et al (2013a) Type I to type II ovarian carcinoma progression: mutant Trp53 or Pik3ca confers a more aggressive tumor phenotype in a mouse model of ovarian cancer. Am J Pathol 182:1391–1399PubMedPubMedCentralCrossRefGoogle Scholar
  368. Wu X et al (2013b) Long chain fatty Acyl-CoA synthetase 4 is a biomarker for and mediator of hormone resistance in human breast cancer. PLoS One 8:e77060–e77060PubMedPubMedCentralCrossRefGoogle Scholar
  369. Wu H et al (2018) Here, there, and everywhere: the importance of ER membrane contact sites. Science 361, eaan5835PubMedPubMedCentralCrossRefGoogle Scholar
  370. Xi J et al (2019) GLS1 promotes proliferation in hepatocellular carcinoma cells via AKT/GSK3β/CyclinD1 pathway. Exp Cell Res 381:1–9PubMedCrossRefGoogle Scholar
  371. Xiang L et al (2019) Glutaminase 1 expression in colorectal cancer cells is induced by hypoxia and required for tumor growth, invasion, and metastatic colonization. Cell Death Dis 10:40–40PubMedPubMedCentralCrossRefGoogle Scholar
  372. Xintaropoulou C et al (2018) Expression of glycolytic enzymes in ovarian cancers and evaluation of the glycolytic pathway as a strategy for ovarian cancer treatment. BMC Cancer 18:636–636PubMedPubMedCentralCrossRefGoogle Scholar
  373. Xu N et al (2012) The FATP1-DGAT2 complex facilitates lipid droplet expansion at the ER-lipid droplet interface. J Cell Biol 198:895–911PubMedPubMedCentralCrossRefGoogle Scholar
  374. Xu S et al (2013) CD36 enhances fatty acid uptake by increasing the rate of intracellular esterification but not transport across the plasma membrane. Biochemistry 52:7254–7261PubMedCrossRefGoogle Scholar
  375. Xu W et al (2018a) Crosstalk of protein kinase C ε with Smad2/3 promotes tumor cell proliferation in prostate cancer cells by enhancing aerobic glycolysis. Cell Mol Life Sci 75:4583–4598PubMedCrossRefGoogle Scholar
  376. Xu Y et al (2018b) miR-27b-3p is involved in doxorubicin resistance of human anaplastic thyroid cancer cells via targeting peroxisome proliferator-activated receptor gamma. Basic Clin Pharmacol Toxicol 123:670–677PubMedCrossRefGoogle Scholar
  377. Yan S-X et al (2013) Effect of antisense oligodeoxynucleotides glucose transporter-1 on enhancement of radiosensitivity of laryngeal carcinoma. Int J Med Sci 10:1375–1386PubMedPubMedCentralCrossRefGoogle Scholar
  378. Yan S et al (2015) Long-chain acyl-CoA synthetase in fatty acid metabolism involved in liver and other diseases: an update. World J Gastroenterol 21:3492–3498PubMedPubMedCentralCrossRefGoogle Scholar
  379. Yan X et al (2017) Eugenol inhibits oxidative phosphorylation and fatty acid oxidation via downregulation of c-Myc/PGC-1β/ERRα signaling pathway in MCF10A-ras cells. Sci Rep 7:12920–12920PubMedPubMedCentralCrossRefGoogle Scholar
  380. Yang C et al (2014) Glutamine oxidation maintains the TCA cycle and cell survival during impaired mitochondrial pyruvate transport. Mol Cell 56:414–424PubMedPubMedCentralCrossRefGoogle Scholar
  381. Yang L et al (2016) Targeting stromal glutamine synthetase in tumors disrupts tumor microenvironment-regulated cancer cell growth. Cell Metab 24:685–700PubMedPubMedCentralCrossRefGoogle Scholar
  382. Yang P et al (2018) Dietary oleic acid-induced CD36 promotes cervical cancer cell growth and metastasis via up-regulation Src/ERK pathway. Cancer Lett 438:76–85PubMedCrossRefGoogle Scholar
  383. Yang H et al (2019) Roles of GLUT-1 and HK-II expression in the biological behavior of head and neck cancer. Oncotarget 10:3066–3083PubMedPubMedCentralGoogle Scholar
  384. Yang-Hartwich Y et al (2014) p53 protein aggregation promotes platinum resistance in ovarian cancer. Oncogene 34:3605PubMedCrossRefGoogle Scholar
  385. Yi W et al (2012) Phosphofructokinase 1 glycosylation regulates cell growth and metabolism. Science 337:975–980PubMedPubMedCentralCrossRefGoogle Scholar
  386. Yin N et al (2004) Molecular mechanisms involved in the growth stimulation of Breast cancer cells by leptin. Cancer Res 64:5870–5875PubMedCrossRefGoogle Scholar
  387. Yin X et al (2017) ID1 promotes hepatocellular carcinoma proliferation and confers chemoresistance to oxaliplatin by activating pentose phosphate pathway. J Exp Clin Cancer Res 36:166–166PubMedPubMedCentralCrossRefGoogle Scholar
  388. You J et al (2017) Cystathionine- γ-lyase promotes process of breast cancer in association with STAT3 signaling pathway. Oncotarget 8:65677–65686PubMedPubMedCentralGoogle Scholar
  389. Yu L et al (2018) Autophagy pathway: cellular and molecular mechanisms. Autophagy 14:207–215PubMedCrossRefGoogle Scholar
  390. Yu W et al (2019) SIRT6 promotes the Warburg effect of papillary thyroid cancer cell BCPAP through reactive oxygen species. Onco Targets Ther 12:2861–2868PubMedPubMedCentralCrossRefGoogle Scholar
  391. Zaidi N et al (2012) ATP-citrate lyase: a key player in cancer metabolism. Cancer Res 72:3709–3714PubMedCrossRefGoogle Scholar
  392. Zanotto-Filho A et al (2016) Alkylating agent-induced NRF2 blocks endoplasmic reticulum stress-mediated Apoptosis via control of glutathione pools and protein thiol Homeostasis. Mol Cancer Ther 15:3000–3014PubMedPubMedCentralCrossRefGoogle Scholar
  393. Zhan L et al (2012a) Regulatory role of KEAP1 and NRF2 in PPARγ expression and chemoresistance in human non-small-cell lung carcinoma cells. Free Radic Biol Med 53:758–768PubMedPubMedCentralCrossRefGoogle Scholar
  394. Zhan T et al (2012b) Overexpressed FATP1, ACSVL4/FATP4 and ACSL1 increase the cellular fatty acid uptake of 3T3-L1 adipocytes but are localized on intracellular membranes. PLoS One 7:e45087–e45087PubMedPubMedCentralCrossRefGoogle Scholar
  395. Zhang W et al (2012) Stromal control of cystine metabolism promotes cancer cell survival in chronic lymphocytic leukaemia. Nat Cell Biol 14:276–286PubMedPubMedCentralCrossRefGoogle Scholar
  396. Zhang J et al (2014) Asparagine plays a critical role in regulating cellular adaptation to glutamine depletion. Mol Cell 56:205–218PubMedPubMedCentralCrossRefGoogle Scholar
  397. Zhang D et al (2015) Metabolic reprogramming of cancer-associated fibroblasts by IDH3α downregulation. Cell Rep 10:1335–1348PubMedCrossRefGoogle Scholar
  398. Zhang C et al (2016) Glutaminase 2 is a novel negative regulator of small GTPase Rac1 and mediates p53 function in suppressing metastasis. elife 5:e10727–e10727PubMedPubMedCentralCrossRefGoogle Scholar
  399. Zhang B et al (2017) IL-17A enhances microglial response to OGD by regulating p53 and PI3K/Akt pathways with involvement of ROS/HMGB1. Front Mol Neurosci 10:271–271PubMedPubMedCentralCrossRefGoogle Scholar
  400. Zhang S et al (2018a) Acetyl-CoA synthetase 2 enhances tumorigenesis and is indicative of a poor prognosis for patients with renal cell carcinoma. Urol Oncol Semin Orig Investig 36:243.e249–243.e220Google Scholar
  401. Zhang M et al (2018b) Adipocyte-derived lipids mediate melanoma progression via FATP proteins. Cancer Discov 8:1006–1025PubMedPubMedCentralCrossRefGoogle Scholar
  402. Zhang X et al (2019a) LncRNA TINCR/microRNA-107/CD36 regulates cell proliferation and apoptosis in colorectal cancer via PPAR signaling pathway based on bioinformatics analysis. In Biol Chem, pp 663PubMedCrossRefGoogle Scholar
  403. Zhang Z-G et al (2019b) KDM5B promotes breast cancer cell proliferation and migration via AMPK-mediated lipid metabolism reprogramming. Exp Cell Res 379:182–190PubMedCrossRefGoogle Scholar
  404. Zhao H et al (2016) Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism. elife 5:e10250–e10250PubMedPubMedCentralCrossRefGoogle Scholar
  405. Zhao W et al (2018) LINK-A promotes cell proliferation through the regulation of aerobic glycolysis in non-small-cell lung cancer. Onco Targets Ther 11:6071–6080PubMedPubMedCentralCrossRefGoogle Scholar
  406. Zheng G-F et al (2015) Unfolded protein response mediated JNK/AP-1 signal transduction, a target for ovarian cancer treatment. Int J Clin Exp Pathol 8:6505–6511PubMedPubMedCentralGoogle Scholar
  407. Zhong J et al (2010) Temporal profiling of the secretome during adipogenesis in humans. J Proteome Res 9:5228–5238PubMedPubMedCentralCrossRefGoogle Scholar
  408. Zhou Y et al (2013) ATP citrate lyase mediates resistance of colorectal cancer cells to SN38. Mol Cancer Ther 12:2782–2791PubMedPubMedCentralCrossRefGoogle Scholar
  409. Zhou J et al (2019) Oncoprotein LAMTOR5 activates GLUT1 Via upregulating NF-κB in liver cancer. Open Med (Wars) 14:264–270CrossRefGoogle Scholar
  410. Zhu H et al (2018) Cystathionine β-Synthase in physiology and cancer. Biomed Res Int 2018:3205125–3205125PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.CEDOC, Chronic Diseases Research Centre, NOVA Medical School | Faculdade de Ciências MédicasUniversidade NOVA de LisboaLisbonPortugal
  2. 2.Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG)LisbonPortugal

Personalised recommendations