Glycolytic Pathway as a Target for Tumor Inhibition

  • Weiqin Lu
  • Peng Huang
Part of the Cancer Drug Discovery and Development book series (CDD&D)


It has been known for decades that cancer cells exhibit elevated aerobic glycolysis, a phenomenon first observed by Otto Warburg. The imaging technique 18fluoro-deoxyglucose-positron emission tomography (FDG-PET) widely used in clinical diagnosis of cancer is based on the increased glucose uptake by cancer cells, likely due to a significant increase in glucose flow into the glycolytic pathway to generate ATP and conversion to other metabolic intermediates and building blocks for cell growth and proliferation. Furthermore, the increased glucose uptake in cancer tissues seems correlated with tumor aggressiveness and poor prognosis. Such profound metabolic alterations suggest that cancer cells may prefer to use glycolysis for their proliferative and survival advantage. Recent studies have begun to elucidate the molecular mechanisms underlying these metabolic alterations, and provide important new insights into the mechanistic links between oncogenic signals and metabolic regulation. Importantly, targeted inhibition of glycolysis and its regulatory pathways may provide exciting opportunities for the development of therapeutic strategies to preferentially kill cancer cells. This chapter will summarize our current understanding of glycolytic alterations in cancer cells and the relevant regulatory mechanisms, and discuss possible therapeutic strategies that exploit the metabolic abnormalities in cancer to preferentially kill malignant cells.


Pentose Phosphate Pathway Glycolytic Enzyme Glycolytic Pathway Metabolic Intermediate Aerobic Glycolysis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Ahmad IM, Aykin-Burns N, Sim JE, Walsh SA, Higashikubo R, Buettner GR, Venkataraman S, Mackey MA, Flanagan SW, Oberley LW et al (2005) Mitochondrial O2*- and H2O2 mediate glucose deprivation-induced stress in human cancer cells. J Biol Chem 280:4254–4263.PubMedCrossRefGoogle Scholar
  2. Altenberg B, Greulich KO (2004) Genes of glycolysis are ubiquitously overexpressed in 24 cancer classes. Genomics 84:1014–1020.PubMedCrossRefGoogle Scholar
  3. Bardeesy N, Sinha M, Hezel AF, Signoretti,S, Hathaway NA, Sharpless NE, Loda,M, Carrasco DR, DePinho RA (2002) Loss of the Lkb1 tumour suppressor provokes intestinal polyposis but resistance to transformation. Nature 419:162–167.PubMedCrossRefGoogle Scholar
  4. Baysal BE, Ferrell RE, Willett-Brozick JE, Lawrence EC, Myssiorek D, Bosch A, van der Mey A, Taschner PE, Rubinstein WS, Myers EN et al (2000) Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science (New York, NY) 287:848–851.PubMedCrossRefGoogle Scholar
  5. Bensaad K, Tsuruta A, Selak MA, Vidal MN, Nakano K, Bartrons R, Gottlieb E, Vousden KH (2006) TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell 126:107–120.PubMedCrossRefGoogle Scholar
  6. Bonnet S, Archer SL, Allalunis-Turner J, Haromy A, Beaulieu C, Thompson R, Lee CT, Lopaschuk GD, Puttagunta L, Bonnet S et al (2007) A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell 11:37–51.PubMedCrossRefGoogle Scholar
  7. Brown RS, Goodman TM, Zasadny KR, Greenson JK, Wahl RL (2002) Expression of hexokinase II and Glut-1 in untreated human breast cancer. Nuclear Med Biol 29:443–453.CrossRefGoogle Scholar
  8. Budihardjo II, Walker DL, Svingen PA, Buckwalter CA, Desnoyers S, Eckdahl S, Shah GM, Poirier GG, Reid JM, Ames MM et al (1998) 6-Aminonicotinamide sensitizes human tumor cell lines to cisplatin. Clin Cancer Res 4:117–130.PubMedGoogle Scholar
  9. Bui T, Thompson CB (2006) Cancer’s sweet tooth. Cancer Cell 9:419–420.PubMedCrossRefGoogle Scholar
  10. Cairns RA, Papandreou I, Sutphin PD, Denko NC (2007) Metabolic targeting of hypoxia and HIF1 in solid tumors can enhance cytotoxic chemotherapy. Proc Natl Acad Sci USA 104:9445–9450.Google Scholar
  11. Cao W, Yacoub S, Shiverick KT, Namiki K, Sakai Y, Porvasnik S, Urbanek C, Rosser CJ (2008) Dichloroacetate (DCA) sensitizes both wild-type and over expressing Bcl-2 prostate cancer cells in vitro to radiation. Prostate 68:1223–1231.PubMedCrossRefGoogle Scholar
  12. Carew JS, Huang P (2002) Mitochondrial defects in cancer. Mol Cancer 1:9.PubMedCrossRefGoogle Scholar
  13. Carew JS, Zhou Y, Albitar M, Carew JD, Keating MJ, Huang P (2003) Mitochondrial DNA mutations in primary leukemia cells after chemotherapy: clinical significance and therapeutic implications. Leukemia 17:1437–1447.PubMedCrossRefGoogle Scholar
  14. Cavalli LR, Liang BC (1998) Mutagenesis, tumorigenicity, and apoptosis: are the mitochondria involved? Mutat Res 398:19–26.PubMedCrossRefGoogle Scholar
  15. Chen Z, Lu W, Garcia-Prieto C, Huang P (2007) The Warburg effect and its cancer therapeutic implications. J Bioenerg Biomembr 39:267–274.PubMedCrossRefGoogle Scholar
  16. Chen Z, Zhang H, Lu W, Huang P (2009) Role of mitochondria-associated hexokinase II in cancer cell death induced by 3-bromopyruvate. Biochim et Biophys Acta 1787:553–560.CrossRefGoogle Scholar
  17. Christofk HR, Vander Heiden MG, Wu N, Asara JM, Cantley LC (2008) Pyruvate kinase M2 is a phosphotyrosine-binding protein. Nature 452:181–186.PubMedCrossRefGoogle Scholar
  18. Cidad P, Almeida A, Bolanos JP (2004) Inhibition of mitochondrial respiration by nitric oxide rapidly stimulates cytoprotective GLUT3-mediated glucose uptake through 5’-AMP-activated protein kinase. Biochem J 384:629–636.PubMedCrossRefGoogle Scholar
  19. Cockman ME, Masson N, Mole DR, Jaakkola P, Chang GW, Clifford SC, Maher ER, Pugh CW, Ratcliffe PJ, Maxwell PH (2000) Hypoxia inducible factor-alpha binding and ubiquitylation by the von Hippel-Lindau tumor suppressor protein. J Biol Chem 275:25733–25741.PubMedCrossRefGoogle Scholar
  20. Comin-Anduix B, Boren J, Martinez S, Moro C, Centelles JJ, Trebukhina R, Petushok N, Lee WN, Boros LG, Cascante M (2001) The effect of thiamine supplementation on tumour proliferation. A metabolic control analysis study. Eur J Biochem/FEBS 268:4177–4182.CrossRefGoogle Scholar
  21. Coy JF, Dressler D, Wilde J, Schubert P (2005) Mutations in the transketolase-like gene TKTL1: clinical implications for neurodegenerative diseases, diabetes and cancer. Clin Lab 51:257–273.PubMedGoogle Scholar
  22. Czernin J, Phelps ME (2002) Positron emission tomography scanning: current and future applications. Annu Rev Med 53:89–112.PubMedCrossRefGoogle Scholar
  23. Dang CV (1999) c-Myc target genes involved in cell growth, apoptosis, and metabolism. Mol Cell Biol 19:1–11.PubMedGoogle Scholar
  24. Dang CV, Kim JW, Gao P, Yustein J (2008) The interplay between MYC and HIF in cancer. Nat Rev 8:51–56.CrossRefGoogle Scholar
  25. Dang CV, Li F, Lee LA (2005) Could MYC induction of mitochondrial biogenesis be linked to ROS production and genomic instability? Cell Cycle 4:1465–1466.PubMedCrossRefGoogle Scholar
  26. Dang CV, Semenza GL (1999) Oncogenic alterations of metabolism. Trends Biochem Sci 24:68–72.PubMedCrossRefGoogle Scholar
  27. De Lena M, Lorusso V, Latorre A, Fanizza G, Gargano G, Caporusso L, Guida M, Catino A, Crucitta E, Sambiasi D et al (2001) Paclitaxel, cisplatin and lonidamine in advanced ovarian cancer. A phase II study. Eur J Cancer 37:364–368.PubMedCrossRefGoogle Scholar
  28. DeBerardinis RJ, Lum JJ, Hatzivassiliou G, Thompson CB (2008a) The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab 7:11–20.PubMedCrossRefGoogle Scholar
  29. Deberardinis RJ, Sayed N, Ditsworth D, Thompson CB (2008b) Brick by brick: metabolism and tumor cell growth. Curr Opin Genet Dev 18:54–61.PubMedCrossRefGoogle Scholar
  30. Denko NC (2008) Hypoxia, HIF1 and glucose metabolism in the solid tumour. Nat Rev 8:705–713.CrossRefGoogle Scholar
  31. Di Cosimo S, Ferretti G, Papaldo P, Carlini P, Fabi A, Cognetti F (2003) Lonidamine: efficacy and safety in clinical trials for the treatment of solid tumors. Drugs Today (Barc) 39:157–174.CrossRefGoogle Scholar
  32. Dombrauckas JD, Santarsiero BD, Mesecar AD (2005) Structural basis for tumor pyruvate kinase M2 allosteric regulation and catalysis. Biochemistry 44:9417–9429.PubMedCrossRefGoogle Scholar
  33. Elstrom RL, Bauer DE, Buzzai M, Karnauskas R, Harris MH, Plas DR, Zhuang H, Cinalli RM, Alavi A, Rudin CM et al (2004) Akt stimulates aerobic glycolysis in cancer cells. Cancer Res 64:3892–3899.PubMedCrossRefGoogle Scholar
  34. Engelman JA, Chen L, Tan X, Crosby K, Guimaraes AR, Upadhyay R, Maira M, McNamara K, Perera SA, Song Y et al (2008) Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat Med 14:1351–1356.PubMedCrossRefGoogle Scholar
  35. Evans MJ, Saghatelian A, Sorensen EJ, Cravatt BF (2005) Target discovery in small-molecule cell-based screens by in situ proteome reactivity profiling. Nat Biotechnol 23:1303–1307.PubMedCrossRefGoogle Scholar
  36. Fantin VR, St-Pierre J, Leder P (2006) Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance. Cancer Cell 9:425–434.PubMedCrossRefGoogle Scholar
  37. Floridi A, Bruno T, Miccadei S, Fanciulli M, Federico A, Paggi MG (1998) Enhancement of doxorubicin content by the antitumor drug lonidamine in resistant Ehrlich ascites tumor cells through modulation of energy metabolism. Biochem Pharmacol 56:841–849.PubMedCrossRefGoogle Scholar
  38. Frezza C, Gottlieb E (2009) Mitochondria in cancer: not just innocent bystanders. Semin Cancer Biol 19:4–11.PubMedCrossRefGoogle Scholar
  39. Gatenby RA (1995) The potential role of transformation-induced metabolic changes in tumor-host interaction. Cancer Res 55:4151–4156.PubMedGoogle Scholar
  40. Gatenby RA, Gawlinski ET (1996) A reaction-diffusion model of cancer invasion. Cancer Res 56:5745–5753.PubMedGoogle Scholar
  41. Gatenby RA, Gawlinski ET, Gmitro AF, Kaylor B, Gillies RJ (2006) Acid-mediated tumor invasion: a multidisciplinary study. Cancer Res 66:5216–5223.PubMedCrossRefGoogle Scholar
  42. Gatenby RA, Gillies RJ (2004) Why do cancers have high aerobic glycolysis? Nat Rev 4:891–899.CrossRefGoogle Scholar
  43. Geschwind JF, Georgiades CS, Ko YH, Pedersen PL (2004) Recently elucidated energy catabolism pathways provide opportunities for novel treatments in hepatocellular carcinoma. Expert Rev Anticancer Ther 4:449–457.PubMedCrossRefGoogle Scholar
  44. Godoy A, Ulloa V, Rodriguez F, Reinicke K, Yanez AJ, Garcia Mde L, Medina RA, Carrasco M, Barberis S, Castro T et al (2006) Differential subcellular distribution of glucose transporters GLUT1-6 and GLUT9 in human cancer: ultrastructural localization of GLUT1 and GLUT5 in breast tumor tissues. J Cell Physiol 207:614–627.PubMedCrossRefGoogle Scholar
  45. Golshani-Hebroni SG, Bessman SP (1997) Hexokinase binding to mitochondria: a basis for proliferative energy metabolism. J Bioenerg Biomembr 29:331–338.PubMedCrossRefGoogle Scholar
  46. Gottlieb TM, Leal JF, Seger R, Taya Y, Oren M (2002) Cross-talk between Akt, p53 and Mdm2: possible implications for the regulation of apoptosis. Oncogene 21:1299–1303.PubMedCrossRefGoogle Scholar
  47. Gottschalk S, Anderson N, Hainz C, Eckhardt SG, Serkova NJ (2004) Imatinib (STI571)-mediated changes in glucose metabolism in human leukemia BCR-ABL-positive cells. Clin Cancer Res 10:6661–6668.PubMedCrossRefGoogle Scholar
  48. Green DR, Chipuk JE (2006) p53 and metabolism: inside the TIGAR. Cell 126:30–32.PubMedCrossRefGoogle Scholar
  49. Gurumurthy S, Hezel AF, Sahin E, Berger JH, Bosenberg MW, Bardeesy N (2008) LKB1 deficiency sensitizes mice to carcinogen-induced tumorigenesis. Cancer Res 68:55–63.PubMedCrossRefGoogle Scholar
  50. Haberkorn U, Strauss LG, Reisser C, Haag D, Dimitrakopoulou A, Ziegler S, Oberdorfer F, Rudat V, van Kaick G (1991) Glucose uptake, perfusion, and cell proliferation in head and neck tumors: relation of positron emission tomography to flow cytometry. J Nucl Med 32:1548–1555.PubMedGoogle Scholar
  51. Halabe Bucay A (2007) The biological significance of cancer: mitochondria as a cause of cancer and the inhibition of glycolysis with citrate as a cancer treatment. Med Hypotheses 69:826–828.PubMedCrossRefGoogle Scholar
  52. Hao HX, Khalimonchuk O, Schraders M, Dephoure N, Bayley JP, Kunst H, Devilee P, Cremers CW, Schiffman JD, Bentz BG et al (2009) SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma. Science (New York, NY) 325:1139–1142.Google Scholar
  53. Hardie DG (2007) AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nat Rev Mol Cell Biol 8:774–785.PubMedCrossRefGoogle Scholar
  54. Hardie DG, Pan DA (2002) Regulation of fatty acid synthesis and oxidation by the AMP-activated protein kinase. Biochem Soc Trans 30:1064–1070.PubMedCrossRefGoogle Scholar
  55. Hawley SA, Boudeau J, Reid JL, Mustard KJ, Udd L, Makela TP, Alessi DR, Hardie DG (2003) Complexes between the LKB1 tumor suppressor, STRAD alpha/beta and MO25 alpha/beta are upstream kinases in the AMP-activated protein kinase cascade. J Biol 2:28.PubMedCrossRefGoogle Scholar
  56. Heinrich PC, Morris HP, Weber G (1976) Behavior of transaldolase (EC and transketolase (EC activities in normal, neoplastic, differentiating, and regenerating liver. Cancer Res 36:3189–3197.PubMedGoogle Scholar
  57. Herrmann PC, Gillespie JW, Charboneau L, Bichsel VE, Paweletz CP, Calvert VS, Kohn EC, Emmert-Buck MR, Liotta LA, Petricoin EF, 3rd (2003) Mitochondrial proteome: altered cytochrome c oxidase subunit levels in prostate cancer. Proteomics 3:1801–1810.PubMedCrossRefGoogle Scholar
  58. Hockel M, Knoop C, Schlenger K, Vorndran B, Baussmann E, Mitze M, Knapstein PG, Vaupel P (1993) Intratumoral pO2 predicts survival in advanced cancer of the uterine cervix. Radiother Oncol 26:45–50.PubMedCrossRefGoogle Scholar
  59. Hockel M, Vaupel P (2003) Oxygenation of cervix cancers: impact of clinical and pathological parameters. Adv Exp Med Biol 510:31–35.PubMedCrossRefGoogle Scholar
  60. Hove H, Rye Clausen M, Brobech Mortensen P (1993) Lactate and pH in faeces from patients with colonic adenomas or cancer. Gut 34:625–629.PubMedCrossRefGoogle Scholar
  61. Hu LH, Yang JH, Zhang DT, Zhang S, Wang L, Cai PC, Zheng JF, Huang JS (2007) The TKTL1 gene influences total transketolase activity and cell proliferation in human colon cancer LoVo cells. Anticancer Drugs 18:427–433.PubMedCrossRefGoogle Scholar
  62. Inoki K, Zhu T, Guan KL (2003) TSC2 mediates cellular energy response to control cell growth and survival. Cell 115:577–590.PubMedCrossRefGoogle Scholar
  63. Isaacs JS, Jung YJ, Mole DR, Lee S, Torres-Cabala C, Chung YL, Merino M, Trepel J, Zbar B, Toro J et al (2005) HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability. Cancer Cell 8:143–153.PubMedCrossRefGoogle Scholar
  64. Ishikawa K, Takenaga K, Akimoto M, Koshikawa N, Yamaguchi A, Imanishi H, Nakada K, Honma Y, Hayashi J (2008) ROS-generating mitochondrial DNA mutations can regulate tumor cell metastasis. Science (New York, NY) 320:661–664.PubMedCrossRefGoogle Scholar
  65. Isidoro A, Martinez M, Fernandez PL, Ortega AD, Santamaria G, Chamorro M, Reed JC, Cuezva JM (2004) Alteration of the bioenergetic phenotype of mitochondria is a hallmark of breast, gastric, lung and oesophageal cancer. Biochem J 378:17–20.PubMedCrossRefGoogle Scholar
  66. Ji H, Ramsey MR, Hayes DN, Fan C, McNamara K, Kozlowski P, Torrice C, Wu MC, Shimamura T, Perera SA et al (2007) LKB1 modulates lung cancer differentiation and metastasis. Nature 448:807–810.PubMedCrossRefGoogle Scholar
  67. Kahn BB, Alquier T, Carling D, Hardie DG (2005) AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. Cell Metab 1:15–25.PubMedCrossRefGoogle Scholar
  68. Kim JW, Dang CV (2006) Cancer’s molecular sweet tooth and the Warburg effect. Cancer Res 66:8927–8930.PubMedCrossRefGoogle Scholar
  69. Kim JW, Zeller KI, Wang Y, Jegga AG, Aronow BJ, O’Donnell KA, Dang CV (2004) Evaluation of myc E-box phylogenetic footprints in glycolytic genes by chromatin immunoprecipitation assays. Mol Cell Biol 24:5923–5936.PubMedCrossRefGoogle Scholar
  70. Ko YH, Pedersen PL, Geschwind JF (2001) Glucose catabolism in the rabbit VX2 tumor model for liver cancer: characterization and targeting hexokinase. Cancer Lett 173:83–91.PubMedCrossRefGoogle Scholar
  71. Kole HK, Resnick RJ, Van Doren M, Racker E (1991) Regulation of 6-phosphofructo-1-kinase activity in ras-transformed rat-1 fibroblasts. Arch Biochem Biophys 286:586–590.PubMedCrossRefGoogle Scholar
  72. Kondoh H, Lleonart ME, Gil J, Wang J, Degan P, Peters G, Martinez D, Carnero A, Beach D (2005) Glycolytic enzymes can modulate cellular life span. Cancer Res 65:177–185.PubMedGoogle Scholar
  73. Krebs HA (1970a) The history of the tricarboxylic acid cycle. Perspect Biol Med 14:154–170.PubMedGoogle Scholar
  74. Krebs HA (1970b) Rate control of the tricarboxylic acid cycle. Adv Enzyme Regul 8:335–353.PubMedCrossRefGoogle Scholar
  75. Kuhajda FP (2000) Fatty-acid synthase and human cancer: new perspectives on its role in tumor biology. Nutrition 16:202–208.PubMedCrossRefGoogle Scholar
  76. Kuhajda FP, Jenner K, Wood FD, Hennigar RA, Jacobs LB, Dick JD, Pasternack GR (1994) Fatty acid synthesis: a potential selective target for antineoplastic therapy. Proc Natl Acad Sci USA 91:6379–6383.PubMedCrossRefGoogle Scholar
  77. Kuo W, Lin J, Tang TK (2000) Human glucose-6-phosphate dehydrogenase (G6PD) gene transforms NIH 3T3 cells and induces tumors in nude mice. Int J Cancer 85:857–864.PubMedCrossRefGoogle Scholar
  78. Langbein S, Frederiks WM, Hausen AZ, Popa J, Lehmann J, Weiss C, Alken P, Coy JF (2008) Metastasis is promoted by a bioenergetic switch: new targets for progressive renal cell cancer. Int J Cancer 122:2422–2428.PubMedCrossRefGoogle Scholar
  79. Langbein S, Zerilli M, Zur Hausen A, Staiger W, Rensch-Boschert K, Lukan N, Popa J, Ternullo MP, Steidler A, Weiss C et al (2006) Expression of transketolase TKTL1 predicts colon and urothelial cancer patient survival: Warburg effect reinterpreted. Br J Cancer 94:578–585.PubMedCrossRefGoogle Scholar
  80. Li D, Yeung SC, Hassan MM, Konopleva M, Abbruzzese JL (2009) Antidiabetic therapies affect risk of pancreatic cancer. Gastroenterology 137:482–488.PubMedCrossRefGoogle Scholar
  81. Lim KH, Counter CM (2005) Reduction in the requirement of oncogenic Ras signaling to activation of PI3K/AKT pathway during tumor maintenance. Cancer Cell 8:381–392.PubMedCrossRefGoogle Scholar
  82. Little CD, Nau MM, Carney DN, Gazdar AF, Minna JD (1983) Amplification and expression of the c-myc oncogene in human lung cancer cell lines. Nature 306:194–196.PubMedCrossRefGoogle Scholar
  83. Lopez-Lazaro M (2008) The warburg effect: why and how do cancer cells activate glycolysis in the presence of oxygen? Anticancer Agents Med Chem 8:305–312.PubMedCrossRefGoogle Scholar
  84. Lu H, Forbes RA, Verma A (2002) Hypoxia-inducible factor 1 activation by aerobic glycolysis implicates the Warburg effect in carcinogenesis. J Biol Chem 277:23111–23115.PubMedCrossRefGoogle Scholar
  85. Majewski N, Nogueira V, Bhaskar P, Coy PE, Skeen JE, Gottlob K, Chandel NS, Thompson CB, Robey RB, Hay N (2004) Hexokinase-mitochondria interaction mediated by Akt is required to inhibit apoptosis in the presence or absence of Bax and Bak. Mol Cell 16:819–830.PubMedCrossRefGoogle Scholar
  86. Mandavilli BS, Santos JH, Van Houten B (2002) Mitochondrial DNA repair and aging. Mutat Res 509:127–151.PubMedCrossRefGoogle Scholar
  87. Maschek G, Savaraj N, Priebe W, Braunschweiger P, Hamilton K, Tidmarsh GF, De Young LR, Lampidis TJ (2004) 2-Deoxy-d-glucose increases the efficacy of adriamycin and paclitaxel in human osteosarcoma and non-small cell lung cancers in vivo. Cancer Res 64:31–34.PubMedCrossRefGoogle Scholar
  88. Mathupala SP, Ko YH, 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.PubMedCrossRefGoogle Scholar
  89. Mathupala SP, Rempel A, 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.PubMedCrossRefGoogle Scholar
  90. Matoba S, Kang JG, Patino WD, Wragg A, Boehm M, Gavrilova O, Hurley PJ, Bunz F, Hwang PM (2006) p53 regulates mitochondrial respiration. Science 312:1650–1653.PubMedCrossRefGoogle Scholar
  91. Milgraum LZ, Witters LA, Pasternack GR, Kuhajda FP (1997) Enzymes of the fatty acid synthesis pathway are highly expressed in in situ breast carcinoma. Clin Cancer Res 3:2115–2120.PubMedGoogle Scholar
  92. Minchenko A, Leshchinsky I, Opentanova I, Sang N, Srinivas V, Armstead V, Caro J (2002) Hypoxia-inducible factor-1-mediated expression of the 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) gene. Its possible role in the Warburg effect. J Biol Chem 277:6183–6187.PubMedCrossRefGoogle Scholar
  93. Mitchell P, Moyle J (1967) Chemiosmotic hypothesis of oxidative phosphorylation. Nature 213:137–139.PubMedCrossRefGoogle Scholar
  94. Newmeyer DD, Ferguson-Miller S (2003) Mitochondria: releasing power for life and unleashing the machineries of death. Cell 112:481–490.PubMedCrossRefGoogle Scholar
  95. Ohta S (2006) Contribution of somatic mutations in the mitochondrial genome to the development of cancer and tolerance against anticancer drugs. Oncogene 25:4768–4776.PubMedCrossRefGoogle Scholar
  96. Olgun A, Akman S, Serdar MA, Kutluay T (2002) Oxidative phosphorylation enzyme complexes in caloric restriction. Exp Gerontol 37:639–645.PubMedCrossRefGoogle Scholar
  97. Ookhtens M, Kannan R, Lyon I, Baker N (1984) Liver and adipose tissue contributions to newly formed fatty acids in an ascites tumor. Am J Physiol 247:R146–R153.PubMedGoogle Scholar
  98. Osthus RC, Shim H, Kim S, Li Q, Reddy R, Mukherjee M, Xu Y, Wonsey D, Lee LA, Dang CV (2000) Deregulation of glucose transporter 1 and glycolytic gene expression by c-Myc. J Biol Chem 275:21797–21800.PubMedCrossRefGoogle Scholar
  99. Papandreou I, Cairns RA, Fontana L, Lim AL, Denko NC (2006) HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab 3:187–197.PubMedCrossRefGoogle Scholar
  100. Parlo RA, Coleman PS (1986) Continuous pyruvate carbon flux to newly synthesized cholesterol and the suppressed evolution of pyruvate-generated CO2 in tumors: further evidence for a persistent truncated Krebs cycle in hepatomas. Biochim Biophys Acta 886:169–176.PubMedCrossRefGoogle Scholar
  101. Parolin ML, Spriet LL, Hultman E, Matsos MP, Hollidge-Horvat MG, Jones NL, Heigenhauser GJ (2000) Effects of PDH activation by dichloroacetate in human skeletal muscle during exercise in hypoxia. Am J Physiol 279:E752–E761.Google Scholar
  102. Pastorino JG, Hoek JB, Shulga N (2005) Activation of glycogen synthase kinase 3beta disrupts the binding of hexokinase II to mitochondria by phosphorylating voltage-dependent anion channel and potentiates chemotherapy-induced cytotoxicity. Cancer Res 65:10545–10554.PubMedCrossRefGoogle Scholar
  103. Pelicano H, Martin DS, Xu RH, Huang P (2006) Glycolysis inhibition for anticancer treatment. Oncogene 25:4633–4646.PubMedCrossRefGoogle Scholar
  104. Pollard PJ, Briere JJ, Alam NA, Barwell J, Barclay E, Wortham NC, Hunt T, Mitchell M, Olpin S, Moat SJ et al (2005) Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations. Hum Mol Genet 14:2231–2239.PubMedCrossRefGoogle Scholar
  105. Porstmann T, Griffiths B, Chung YL, Delpuech O, Griffiths JR, Downward J, Schulze A (2005) PKB/Akt induces transcription of enzymes involved in cholesterol and fatty acid biosynthesis via activation of SREBP. Oncogene 24:6465–6481.PubMedGoogle Scholar
  106. Poulsen HS, Frederiksen P (1981) Glucose-6-phosphate dehydrogenase activity in human breast cancer. Lack of association with oestrogen receptor content. Acta Pathol Microbiol Scand 89:263–270.Google Scholar
  107. Pozuelo Rubio M, Peggie M, Wong BH, Morrice N, MacKintosh C (2003) 14-3-3s regulate fructose-2,6-bisphosphate levels by binding to PKB-phosphorylated cardiac fructose-2,6-bisphosphate kinase/phosphatase. EMBO J 22:3514–3523.PubMedCrossRefGoogle Scholar
  108. Rais B, Comin B, Puigjaner J, Brandes JL, Creppy E, Saboureau D, Ennamany R, Lee WN, Boros LG, Cascante M (1999) Oxythiamine and dehydroepiandrosterone induce a G1 phase cycle arrest in Ehrlich’s tumor cells through inhibition of the pentose cycle. FEBS Lett 456:113–118.PubMedCrossRefGoogle Scholar
  109. Ramos-Montoya A, Lee WN, Bassilian S, Lim S, Trebukhina RV, Kazhyna MV, Ciudad CJ, Noe V, Centelles JJ, Cascante M (2006) Pentose phosphate cycle oxidative and nonoxidative balance: a new vulnerable target for overcoming drug resistance in cancer. Int J Cancer 119:2733–2741.PubMedCrossRefGoogle Scholar
  110. Rathmell JC, Fox CJ, Plas DR, Hammerman PS, Cinalli RM, Thompson CB (2003) Akt-directed glucose metabolism can prevent Bax conformation change and promote growth factor-independent survival. Mol Cell Biol 23:7315–7328.PubMedCrossRefGoogle Scholar
  111. Ristow M (2006) Oxidative metabolism in cancer growth. Curr Opin Clin Nutr Metab Care 9:339–345.PubMedCrossRefGoogle Scholar
  112. Robey RB, Hay N (2005) Mitochondrial hexokinases: guardians of the mitochondria. Cell cycle (Georgetown, TX) 4:654–658.PubMedCrossRefGoogle Scholar
  113. Robey RB, Hay N (2009) Is Akt the “Warburg kinase”?-Akt-energy metabolism interactions and oncogenesis. Semin Cancer Biol 19:25–31.PubMedCrossRefGoogle Scholar
  114. Rossi S, Graner E, Febbo P, Weinstein L, Bhattacharya N, Onody T, Bubley G, Balk S, Loda M (2003) Fatty acid synthase expression defines distinct molecular signatures in prostate cancer. Mol Cancer Res 1:707–715.PubMedGoogle Scholar
  115. Safran M, Kaelin WG, Jr (2003) HIF hydroxylation and the mammalian oxygen-sensing pathway. J Clin Invest 111:779–783.PubMedGoogle Scholar
  116. Sanchez-Martinez C, Aragon JJ (1997) Analysis of phosphofructokinase subunits and isozymes in ascites tumor cells and its original tissue, murine mammary gland. FEBS Lett 409:86–90.PubMedCrossRefGoogle Scholar
  117. Schornack PA, Gillies RJ (2003) Contributions of cell metabolism and H+ diffusion to the acidic pH of tumors. Neoplasia (New York, NY) 5:135–145.PubMedGoogle Scholar
  118. Schwickert G, Walenta S, Sundfor K, Rofstad EK, Mueller-Klieser W (1995) Correlation of high lactate levels in human cervical cancer with incidence of metastasis. Cancer Res 55:4757–4759.PubMedGoogle Scholar
  119. Scott R, Crooks R, Meldrum C (2008) Gene symbol: STK11. Disease: Peutz-Jeghers syndrome. Hum Genet 124:300.PubMedGoogle Scholar
  120. Seemann MD (2004) PET/CT: fundamental principles. Eur J Med Res 9:241–246.PubMedGoogle Scholar
  121. Selak MA, Armour SM, MacKenzie ED, Boulahbel H, Watson DG, Mansfield KD, Pan Y, Simon MC, Thompson CB, Gottlieb E (2005) Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell 7:77–85.PubMedCrossRefGoogle Scholar
  122. Semenza GL (2003) Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3:721–732.PubMedCrossRefGoogle Scholar
  123. Semenza GL (2007) HIF-1 mediates the Warburg effect in clear cell renal carcinoma. J Bioenerg Biomembr 39:231–234.PubMedCrossRefGoogle Scholar
  124. Sharp FR, Bernaudin M (2004) HIF1 and oxygen sensing in the brain. Nat Rev Neurosci 5:437–448.PubMedCrossRefGoogle Scholar
  125. Shaw RJ (2006) Glucose metabolism and cancer. Curr Opin Cell Biol 18:598–608.PubMedCrossRefGoogle Scholar
  126. Shaw RJ, Bardeesy N, Manning BD, Lopez L, Kosmatka M, DePinho RA, Cantley LC (2004a) The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell 6:91–99.PubMedCrossRefGoogle Scholar
  127. Shaw RJ, Kosmatka M, Bardeesy N, Hurley RL, Witters LA, DePinho RA, Cantley LC (2004b) The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. Proc Natl Acad Sci USA 101:3329–3335.PubMedCrossRefGoogle Scholar
  128. Shi Q, Le X, Wang B, Abbruzzese JL, Xiong Q, He Y, Xie K (2001) Regulation of vascular endothelial growth factor expression by acidosis in human cancer cells. Oncogene 20:3751–3756.PubMedCrossRefGoogle Scholar
  129. Shim H, Dolde C, Lewis BC, Wu CS, Dang G, Jungmann RA, Dalla-Favera R, Dang CV (1997) c-Myc transactivation of LDH-A: implications for tumor metabolism and growth. Proc Natl Acad Sci USA 94:6658–6663.PubMedCrossRefGoogle Scholar
  130. Skulachev VP (1994) Chemiosmotic concept of the membrane bioenergetics: what is already clear and what is still waiting for elucidation? J Bioenerg Biomembr 26:589–598.PubMedCrossRefGoogle Scholar
  131. Smith TA (2000) Mammalian hexokinases and their abnormal expression in cancer. Br J Biomed Sci 57:170–178.PubMedGoogle Scholar
  132. Smith TA, Sharma RI, Thompson AM, Paulin FE (2006) Tumor 18F-FDG incorporation is enhanced by attenuation of P53 function in breast cancer cells in vitro. J Nucl Med 47:1525–1530.PubMedGoogle Scholar
  133. Sonveaux P, Vegran F, Schroeder T, Wergin MC, Verrax J, Rabbani ZN, De Saedeleer CJ, Kennedy KM, Diepart C, Jordan BF et al (2008) Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J Clin Investig 118:3930–3942.PubMedGoogle Scholar
  134. Stacpoole PW, Greene YJ (1992) Dichloroacetate. Diabetes Care 15:785–791.PubMedCrossRefGoogle Scholar
  135. Suter M, Riek U, Tuerk R, Schlattner U, Wallimann T, Neumann D (2006) Dissecting the role of 5’-AMP for allosteric stimulation, activation, and deactivation of AMP-activated protein kinase. J Biol Chem 281:32207–32216.PubMedCrossRefGoogle Scholar
  136. Swinnen JV, Brusselmans K, Verhoeven G (2006) Increased lipogenesis in cancer cells: new ­players, novel targets. Curr Opin Clin Nutr Metab Care 9:358–365.PubMedCrossRefGoogle Scholar
  137. Swinnen JV, Vanderhoydonc F, Elgamal AA, Eelen M, Vercaeren I, Joniau S, Van Poppel H, Baert L, Goossens K, Heyns W et al (2000) Selective activation of the fatty acid synthesis pathway in human prostate cancer. Int J Cancer 88:176–179.PubMedCrossRefGoogle Scholar
  138. Thierbach R, Schulz TJ, Isken F, Voigt A, Mietzner B, Drewes G, von Kleist-Retzow JC, Wiesner RJ, Magnuson MA, Puccio H et al (2005) Targeted disruption of hepatic frataxin expression causes impaired mitochondrial function, decreased life span and tumor growth in mice. Hum Mol Genet 14:3857–3864.PubMedCrossRefGoogle Scholar
  139. Thomas DD, Miranda KM, Colton CA, Citrin D, Espey MG, Wink DA (2003) Heme proteins and nitric oxide (NO): the neglected, eloquent chemistry in NO redox signaling and regulation. Antioxid Redox Signal 5:307–317.PubMedCrossRefGoogle Scholar
  140. Tian WN, Braunstein LD, Apse K, Pang J, Rose M, Tian X, Stanton RC (1999) Importance of glucose-6-phosphate dehydrogenase activity in cell death. Am J Physiol 276:C1121–C1131.PubMedGoogle Scholar
  141. Tomlinson IP, Alam NA, Rowan AJ, Barclay E, Jaeger EE, Kelsell D, Leigh I, Gorman P, Lamlum H, Rahman S et al (2002) Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet 30:406–410.PubMedCrossRefGoogle Scholar
  142. Tong X, Zhao F, Thompson CB (2009) The molecular determinants of de novo nucleotide biosynthesis in cancer cells. Curr Opin Genet Dev 19:32–37.PubMedCrossRefGoogle Scholar
  143. Vander Heiden MG, Cantley LC, Thompson CB (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science (New York, NY) 324:1029–1033.PubMedCrossRefGoogle Scholar
  144. Varshney R, Adhikari JS, Dwarakanath BS (2003) Contribution of oxidative stress to radiosensitization by a combination of 2-DG and 6-AN in human cancer cell line. Ind J Exp Biol 41:1384–1391.Google Scholar
  145. Verma M, Kagan J, Sidransky D, Srivastava S (2003) Proteomic analysis of cancer-cell mitochondria. Nat Rev 3:789–795.CrossRefGoogle Scholar
  146. Vogelstein B, Lane D, Levine AJ (2000) Surfing the p53 network. Nature 408:307–310.PubMedCrossRefGoogle Scholar
  147. Wallace DC (1999) Mitochondrial diseases in man and mouse. Science (New York, NY) 283:1482–1488.PubMedCrossRefGoogle Scholar
  148. Wallace DC (2005) Mitochondria and cancer: Warburg addressed. Cold Spring Harb Symp Quant Biol 70:363–374.PubMedCrossRefGoogle Scholar
  149. Warburg O (1956a) On respiratory impairment in cancer cells. Science 124:269–270.PubMedGoogle Scholar
  150. Warburg O (1956b) On the origin of cancer cells. Science (New York, NY) 123:309–314.PubMedCrossRefGoogle Scholar
  151. Weber WA (2006) Positron emission tomography as an imaging biomarker. J Clin Oncol 24:3282–3292.PubMedCrossRefGoogle Scholar
  152. Woods A, Johnstone SR, Dickerson K, Leiper FC, Fryer LG, Neumann D, Schlattner U, Wallimann T, Carlson M, Carling D (2003) LKB1 is the upstream kinase in the AMP-activated protein kinase cascade. Curr Biol 13:2004–2008.PubMedCrossRefGoogle Scholar
  153. Xie H, Valera VA, Merino MJ, Amato AM, Signoretti S, Linehan WM, Sukhatme VP, Seth P (2009) LDH-A inhibition, a therapeutic strategy for treatment of hereditary leiomyomatosis and renal cell cancer. Mol Cancer Ther 8:626–635.PubMedCrossRefGoogle Scholar
  154. Xu RH, Pelicano H, Zhang H, Giles FJ, Keating MJ, Huang P (2005a) Synergistic effect of targeting mTOR by rapamycin and depleting ATP by inhibition of glycolysis in lymphoma and leukemia cells. Leukemia 19:2153–2158.PubMedCrossRefGoogle Scholar
  155. Xu RH, Pelicano H, Zhou Y, Carew JS, Feng L, Bhalla KN, Keating MJ, Huang P (2005b) Inhibition of glycolysis in cancer cells: a novel strategy to overcome drug resistance associated with mitochondrial respiratory defect and hypoxia. Cancer Res 65:613–621.PubMedCrossRefGoogle Scholar
  156. Yahagi N, Shimano H, Hasegawa K, Ohashi K, Matsuzaka T, Najima Y, Sekiya M, Tomita S, Okazaki,H, Tamura,Y et al (2005) Co-ordinate activation of lipogenic enzymes in hepatocellular carcinoma. Eur J Cancer 41:1316–1322.PubMedCrossRefGoogle Scholar
  157. Yu Y, Deck JA, Hunsaker LA, Deck LM, Royer RE, Goldberg E, Vander Jagt DL (2001) Selective active site inhibitors of human lactate dehydrogenases A4, B4, and C4. Biochem Pharmacol 62:81–89.PubMedCrossRefGoogle Scholar
  158. Zastawny TH, Dabrowska M, Jaskolski T, Klimarczyk M, Kulinski L, Koszela A, Szczesniewicz M, Sliwinska M, Witkowski P, Olinski R (1998) Comparison of oxidative base damage in mitochondrial and nuclear DNA. Free Radical Biol Med 24:722–725.CrossRefGoogle Scholar
  159. Zhang S, Yang JH, Guo CK, Cai PC (2007) Gene silencing of TKTL1 by RNAi inhibits cell proliferation in human hepatoma cells. Cancer Lett 253:108–114.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Department of Molecular PathologyThe University of Texas MD Anderson Cancer CenterHoustonUSA

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