The altered metabolism of cancer cells was recognized and pioneered by the elegant works of Otto Warburg in the 1920s and popularized in the 1950s. Presently, it is well recognized that over sixty percent of all cancers are glycolytic. The Warburg effect or phenomenon is discussed, and the molecular understanding of some of Warburg’s statements is provided with regard to modern knowledge of carcinogenesis. In addition, molecular explanation of aerobic glycolysis of the cancer cell is detailed. Other metabolic alterations of the cancer cell including glutaminolysis and lipogenesis are discussed. The altered citrate metabolism specifically associated with malignant transformation of peripheral zone prostate epithelial cells, and the potential clinical applications of such metabolic alterations conclude this chapter.
- Aerobic Glycolysis
- Fumarate Hydratase
- Glutamine Metabolism
- Citrate Transport Protein
- Citrate Oxidation
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Grana refers to mitochondria.
Altenberg B, and Greulich KO (2004). Genes of glycolysis are ubiquitously overexpressed in 24 cancer classes. Genomics 84, 1014–1020.
Ben-Porath I, Thomson MW, Carey VJ, Ge R, Bell GW, and Regev A (2008). An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. Nat Genet 40, 499–507.
Bensaad K, Tsuruta A, Selak MA, Vidal MN, Nakano K, and Bartrons R (2006). TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell 126, 107–120.
Billin AN, Eilers AL, Queva C, and Ayer DE (1999). Mlx, a novel Max-like BHLHZip protein that interacts with the Max network of transcription factors. J Biol Chem 274, 36344–36350
Billin AN, Eilers AL, Coulter KL, Logan JS, and Ayer DE (2000). MondoA, a novel basic helix-loop-helix-leucine zipper transcriptional activator that constitutes a positive branch of a max-like network. Mol Cell Biol 20, 8845–8854.
Brown GK (2000). Glucose transporters: structure, function and consequences of deficiency. J Inherit Metab Dis 23, 237–246.
Bustamante E, and Pedersen PL (1977). High aerobic glycolysis of rat hepatoma cells in culture: role of mitochondrial hexokinase. Proc Natl Acad Sci USA 74, 3735–3739.
Cai Z, and Semenza GL (2005). PTEN activity is modulated during ischemia and reperfusion: involvement in the induction and decay of preconditioning. Circ Res 97, 1351–1359.
Costello LC, and Franklin RB (2000). The intermediary metabolism of the prostate:a key to understanding the pathogenesis and progression of prostate malignancy. Oncology 59, 269–282.
Costello LC, and Franklin RB (2006). The clinical relevance of the metabolism of prostate cancer; zinc and tumor suppression: connecting the dots. Mol Cancer 5, 17.
Costello LC, and Franklin RB (2009). Prostatic fluid electrolyte composition for the screening of prostate cancer: a potential solution to a major problem. Prostate Cancer Prostatic Dis 12, 17–24.
Costello LC, Franklin RB, and Narayan P (1999). Citrate in the diagnosis of prostate cancer. Prostate 38, 237–245.
Costello LC, Feng P, Milon B, Tan M, and Franklin RB (2004). Role of zinc in the pathogenesis and treatment of prostate cancer: critical issues to resolve. Prostate Cancer Prostatic Dis 7, 111–117.
Costello LC, Franklin RB, Feng P, Tan M, and Bagasra O (2005). Zinc and prostate cancer: a critical scientific, medical, and public interest issue (United States). Cancer Causes Control 16, 901–915.
Crabtree HG (1926). Observations on the carbohydrate metabolism of tumours. Biochem J 23, 536–545.
Dahia PL, Ross KN, Wright ME, et al. (2005). A HIF1alpha regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas. PLoS Genet 1, 72–80.
DeBerardinis RJ, Mancuso A, Daikhin E, 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 USA 104, 19345–19350.
Desouki MM, Geradts J, Milon B, Franklin RB, and Costello LC (2007). hZip2 and hZip3 zinc transporters are down regulated in human prostate adenocarcinomatous glands. Mol Cancer 6, 37.
Feng P, Li T, Guan Z, Franklin RB, and Costello LC (2008). The involvement of Bax in zinc-induced mitochondrial apoptogenesis in malignant prostate cells. Mol Cancer 7, 25.
Franklin RB, and Costello LC (2007). Zinc as an anti-tumor agent in prostate cancer and in other cancers. Arch Biochem Biophys 463, 211–217.
Franklin RB, and Costello LC (2009). The important role of the apoptotic effects of zinc in the development of cancers. J Cell Biochem 106, 750–757.
Fukuda R, Zhang H, Kim JW, et al. (2007). HIF-1 regulates cytochrome oxidase subunits to optimize efficiency of respiration in hypoxic cells. Cell 129, 111–122.
Gallus S, Foschi R, Negri E, et al. (2007). Dietary zinc and prostate cancer risk: a case-control study from Italy. Eur Urol 52, 1052–1056.
Gonzalez A, Peters U, Lampe JW, and White E (2009). Zinc intake from supplements and diet and prostate cancer. Nutr Cancer 61, 206–215.
Guzy RD, Hoyos B, Robin E, et al. (2005). Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing. Cell Metab 1, 401–408.
Guzy RD, Sharma B, Bell E, Chandel NS, and Schumacker PT (2008). Loss of the SdhB, but Not the SdhA, subunit of complex II triggers reactive oxygen species-dependent hypoxia-inducible factor activation and tumorigenesis. Mol Cell Biol 28, 718–731.
Harman D (1956). Aging: a theory based on free radical and radiation chemistry. J Gerontol 11, 298–300.
Hausenloy DJ, Tsang A, Mocanu MM, and Yellon DM (2005). Ischemic preconditioning protects by activating prosurvival kinases at reperfusion. Am J Physiol Heart Circ Physiol 288, H971–976.
Heinz A, Sachs G, and Schafer JA (1981). Evidence for activation of an active electrogenic proton pump in Ehrlich ascites tumor cells during glycolysis. J Membr Biol 61, 143–153.
Hu CJ, Sataur A, Wang L, Chen H, and Simon MC (2007). The N-terminal transactivation domain confers target gene specificity of hypoxia-inducible factors HIF-1alpha and HIF-2alpha. Mol Biol Cell 18, 4528–4542.
Jiang BH, Agani F, Passaniti A, and Semenza GL (1997). V-SRC induces expression of hypoxia-inducible factor 1 (HIF-1) and transcription of genes encoding vascular endothelial growth factor and enolase 1: involvement of HIF-1 in tumor progression. Cancer Res 57, 5328–5335.
Jung JA, Coakley FV, Vigneron DB, et al. (2004). Prostate depiction at endorectal MR spectroscopic imaging: investigation of a standardized evaluation system. Radiology 233, 701–708.
Kaelin WG, Jr. (2002). Molecular basis of the VHL hereditary cancer syndrome. Nat Rev Cancer 2, 673–682.
Kaelin WG (2005). The von Hippel-Lindau tumor suppressor protein: roles in cancer and oxygen sensing. Cold Spring Harb Symp Quant Biol 70, 159–166.
Kim JW, and Dang CV (2005). Multifaceted roles of glycolytic enzymes. Trends Biochem Sci 30, 142–150.
Klimova T, and Chandel NS (2008). Mitochondrial complex III regulates hypoxic activation of HIF. Cell Death Differ 15, 660–666.
Kondoh H, Lleonart ME, Bernard D, and Gil J (2007). Protection from oxidative stress by enhanced glycolysis; a possible mechanism of cellular immortalization. Histol Histopathol 22, 85–90.
Koukourakis MI, Giatromanolaki A, Sivridis E, Gatter KC, and Harris AL (2005). Pyruvate dehydrogenase and pyruvate dehydrogenase kinase expression in non small cell lung cancer and tumor-associated stroma. Neoplasia 7, 1–6.
Laughner E, Taghavi P, Chiles K, Mahon PC, and Semenza GL (2001). HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1alpha (HIF-1alpha) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. Mol Cell Biol 21, 3995–4004.
Li F, Wang Y, Zeller KI, et al. (2005). Myc stimulates nuclearly encoded mitochondrial genes and mitochondrial biogenesis. Mol Cell Biol 25, 6225–6234.
Linehan WM, Walther MM, and Zbar B (2003). The genetic basis of cancer of the kidney. J Urol 170, 2163–2172.
Lopez-Rios F, Sanchez-Arago M, Garcia-Garcia E, et al. (2007). Loss of the mitochondrial bioenergetic capacity underlies the glucose avidity of carcinomas. Cancer Res 67, 9013–9017.
Lu H, Dalgard CL, Mohyeldin A, et al. (2005). Reversible inactivation of HIF-1 prolyl hydroxylases allows cell metabolism to control basal HIF-1. J Biol Chem 280, 41928–41939.
Mathupala SP, Rempel A, and Pedersen PL (1997). Aberrant glycolytic metabolism of cancer cells: a remarkable coordination of genetic, transcriptional, post-translational, and mutational events that lead to a critical role for type II hexokinase. J Bioenerg Biomembr 29, 339–343.
Mathupala SP, Ko YH, and Pedersen PL (2006). Hexokinase II: cancer's double-edged sword acting as both facilitator and gatekeeper of malignancy when bound to mitochondria. Oncogene 25, 4777–4786.
Matoba S, Kang JG, Patino WD, et al. (2006). p53 regulates mitochondrial respiration. Science 312, 1650–1653.
Mayer D, Klimek F, Rempel A, and Bannasch P (1997). Hexokinase expression in liver preneoplasia and neoplasia. Biochem Soc Trans 25, 122–127.
Maynard MA, and Ohh M (2004). Von Hippel-Lindau tumor suppressor protein and hypoxia-inducible factor in kidney cancer. Am J Nephrol 24, 1–13.
McFate T, Mohyeldin A, Lu H, et al. (2008). Pyruvate dehydrogenase complex activity controls metabolic and malignant phenotype in cancer cells. J Biol Chem 283, 22700–22708.
Miquel J, Binnard R, and Fleming JE (1983). Role of metabolic rate and DNA-repair in Drosophila aging: implications for the mitochondrial mutation theory of aging. Exp Gerontol 18, 167–171.
Mocanu MM, Bell RM, and Yellon DM (2002). PI3 kinase and not p42/p44 appears to be implicated in the protection conferred by ischemic preconditioning. J Mol Cell Cardiol 34, 661–668.
Moro L, Arbini AA, Yao JL, et al. (2008). Mitochondrial DNA depletion in prostate epithelial cells promotes anoikis resistance and invasion through activation of PI3K/Akt2. Cell Death Differ.
Murry CE, Jennings RB, and Reimer KA (1986). Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 74, 1124–1136.
Ogawa Y, Kobayashi T, Nishioka A, et al. (2003). Radiation-induced reactive oxygen species formation prior to oxidative DNA damage in human peripheral T cells. Int J Mol Med 11, 149–152.
Osthus RC, Shim H, Kim S, et al. (2000). Deregulation of glucose transporter 1 and glycolytic gene expression by c-Myc. J Biol Chem 275, 21797–21800.
Papandreou I, Cairns RA, Fontana L, Lim AL, and Denko NC (2006). HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab 3, 187–197.
Patel MS, and Korotchkina LG (2001). Regulation of mammalian pyruvate dehydrogenase complex by phosphorylation: complexity of multiple phosphorylation sites and kinases. Exp Mol Med 33, 191–197.
Pedersen PL (2007). Warburg, me and Hexokinase 2: Multiple discoveries of key molecular events underlying one of cancers' most common phenotypes, the “Warburg Effect”, i.e., elevated glycolysis in the presence of oxygen. J Bioenerg Biomembr 39, 211–222.
Pedersen PL, Mathupala S, Rempel A, Geschwind JF, and Ko YH (2002). Mitochondrial bound type II hexokinase: a key player in the growth and survival of many cancers and an ideal prospect for therapeutic intervention. Biochim Biophys Acta 1555, 14–20.
Plas DR, and Thompson CB (2005). Akt-dependent transformation: there is more to growth than just surviving. Oncogene 24, 7435–7442.
Pollard P, Wortham N, Barclay E, et al. (2005a). Evidence of increased microvessel density and activation of the hypoxia pathway in tumours from the hereditary leiomyomatosis and renal cell cancer syndrome. J Pathol 205, 41–49.
Pollard PJ, Briere JJ, Alam NA, et al. (2005b). Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations. Hum Mol Genet 14, 2231–2239.
Pomare EW, Branch WJ, and Cummings JH (1985). Carbohydrate fermentation in the human colon and its relation to acetate concentrations in venous blood. J Clin Invest 75, 1448–1454.
Prahl S, Kueper T, Biernoth T, et al. (2008). Aging skin is functionally anaerobic: importance of coenzyme Q10 for anti aging skin care. Biofactors 32, 245–255.
Prando A, Kurhanewicz J, Borges AP, Oliveira EM, Jr., and Figueiredo E (2005). Prostatic biopsy directed with endorectal MR spectroscopic imaging findings in patients with elevated prostate specific antigen levels and prior negative biopsy findings: early experience. Radiology 236, 903–910.
Rempel A, Bannasch P, and Mayer D (1994). Differences in expression and intracellular distribution of hexokinase isoenzymes in rat liver cells of different transformation stages. Biochim Biophys Acta 1219, 660–668.
Rodriguez-Enriquez S, Juarez O, Rodriguez-Zavala JS, and Moreno-Sanchez R (2001). Multisite control of the Crabtree effect in ascites hepatoma cells. Eur J Biochem 268, 2512–2519.
Sans CL, Satterwhite DJ, Stoltzman CA, Breen KT, and Ayer DE (2006). MondoA-Mlx heterodimers are candidate sensors of cellular energy status: mitochondrial localization and direct regulation of glycolysis. Mol Cell Biol 26, 4863–4871.
Schofield CJ, and Ratcliffe PJ (2005). Signalling hypoxia by HIF hydroxylases. Biochem Biophys Res Commun 338, 617–626.
Semenza GL, and Wang GL (1992). A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol 12, 5447–5454.
Sheta EA, Trout H, Gildea JJ, Harding MA, and Theodorescu D (2001). Cell density mediated pericellular hypoxia leads to induction of HIF-1alpha via nitric oxide and Ras/MAP kinase mediated signaling pathways. Oncogene 20, 7624–7634.
Simon MC (2006). Mitochondrial reactive oxygen species are required for hypoxic HIF alpha stabilization. Adv Exp Med Biol 588, 165–170.
Singh KK, Desouki MM, Franklin RB, and Costello LC (2006). Mitochondrial aconitase and citrate metabolism in malignant and nonmalignant human prostate tissues. Mol Cancer 5, 14.
Sussman I, Erecinska M, and Wilson DF (1980). Regulation of cellular energy metabolism: the Crabtree effect. Biochim Biophys Acta 591, 209–223.
Tian H, McKnight SL, and Russell DW (1997). Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells. Genes Dev 11, 72–82.
Tong H, Chen W, Steenbergen C, and Murphy E (2000). Ischemic preconditioning activates phosphatidylinositol-3-kinase upstream of protein kinase C. Circ Res 87, 309–315.
Uddin S, Siraj AK, Al-Rasheed M, et al. (2008). Fatty acid synthase and AKT pathway signaling in a subset of papillary thyroid cancers. J Clin Endocrinol Metab 93, 4088–4097.
Umbehr M, Bachmann LM, Held U, et al. (2008). Combined Magnetic Resonance Imaging and Magnetic Resonance Spectroscopy Imaging in the Diagnosis of Prostate Cancer: A Systematic Review and Meta-analysis. Eur Urol.
Vanharanta S, Pollard PJ, Lehtonen HJ, et al. (2006). Distinct expression profile in fumarate-hydratase-deficient uterine fibroids. Hum Mol Genet 15, 97–103.
Warburg O (1956). On the origin of cancer cells. Science 123, 309–314.
Wilson JE (1997). An introduction to the isoenzymes of mammalian hexokinase types I-III. Biochem Soc Trans 25, 103–107.
Wilson JE (2003). Isozymes of mammalian hexokinase: structure, subcellular localization and metabolic function. J Exp Biol 206, 2049–2057.
Wise DR, DeBerardinis RJ, Mancuso A, et al. (2008). Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc Natl Acad Sci USA 105, 18782–18787.
Wojtczak L (1996). The Crabtree effect: a new look at the old problem. Acta Biochim Pol 43, 361–368.
Yang X, Borg LA, and Eriksson UJ (1997). Altered metabolism and superoxide generation in neural tissue of rat embryos exposed to high glucose. Am J Physiol 272, E173–180.
Zakian KL, Sircar K, Hricak H, et al. (2005). Correlation of proton MR spectroscopic imaging with gleason score based on step-section pathologic analysis after radical prostatectomy. Radiology 234, 804–814.
Zhang H, Gao P, Fukuda R, et al. (2007). HIF-1 inhibits mitochondrial biogenesis and cellular respiration in VHL-deficient renal cell carcinoma by repression of C-MYC activity. Cancer Cell 11, 407–420.
Zhao ZQ, Corvera JS, Halkos ME, et al. (2003). Inhibition of myocardial injury by ischemic postconditioning during reperfusion: comparison with ischemic preconditioning. Am J Physiol Heart Circ Physiol 285, H579–588.
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Dakubo, G.D. (2010). The Warburg Phenomenon and Other Metabolic Alterations of Cancer Cells. In: Mitochondrial Genetics and Cancer. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-11416-8_2
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