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Metabolic modulation of cancer: a new frontier with great translational potential

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Abstract

Metabolic oncology is an exciting new field in cancer research, offering a new window to cancer’s molecular plasticity and promise for the development of effective, cancer-selective therapies and novel biomarkers. It is based on the realization that cancer’s unique metabolism (known since Warburg’s report in 1923) with suppression of mitochondrial glucose oxidation and upregulation of cytoplasmic glycolysis is not a secondary but a primary event, offering many growth advantages to cancer cells. Many mechanisms have been revealed, including growth factors, oncogenes, and mutations, all contributing to a suppression of mitochondria, similar to what takes place in hypoxia. This suppression leads to inhibition of mitochondria-driven apoptosis, promotes proliferation, and enhances angiogenesis and metastatic potential. A number of molecular tools and small molecules targeting metabolic enzymes, including pyruvate kinase, pyruvate dehydrogenase kinase, isocitrate dehydrogenase, and lactate dehydrogenase, have been developed, inhibiting cancer growth in vitro and in vivo in several cancer types. Several have already entered early-phase trials, a great translational success considering the young age of the field (less than 10 years). Here we review the mechanisms and effects of these metabolic modulators and the rationale for further development. This rapidly accumulating knowledge allows some optimism that this may prove to be a paradigm shift in the way we understand and treat cancer.

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References

  1. Le Tourneau C, Lee JJ, Siu LL (2009) Dose escalation methods in phase I cancer clinical trials. J Natl Cancer Inst 101:708–720

    PubMed Central  PubMed  Google Scholar 

  2. Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, Lydon NB, Kantarjian H, Capdeville R, Ohno-Jones S et al (2001) Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 344:1031–1037

    CAS  PubMed  Google Scholar 

  3. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M et al (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783–792

    CAS  PubMed  Google Scholar 

  4. Wen PY, Kesari S (2008) Malignant gliomas in adults. N Engl J Med 359:492–507

    CAS  PubMed  Google Scholar 

  5. Loureiro R, Mesquita KA, Oliveira PJ, Vega-Naredo I (2013) Mitochondria in cancer stem cells: a target for therapy. Recent Pat Endocr Metab Immune Drug Discov 7:102–114

    CAS  PubMed  Google Scholar 

  6. Warburg O (1923) Metabolism of tumours. Biochem Zeitschr 142:317–333

    CAS  Google Scholar 

  7. Loenarz C, Schofield CJ (2008) Expanding chemical biology of 2-oxoglutarate oxygenases. Nat Chem Biol 4:152–156

    CAS  PubMed  Google Scholar 

  8. Schmid T, Zhou J, Kohl R, Brune B (2004) p300 relieves p53-evoked transcriptional repression of hypoxia-inducible factor-1 (HIF-1). Biochem J 380:289–295

    CAS  PubMed Central  PubMed  Google Scholar 

  9. Vousden KH, Ryan KM (2009) p53 and metabolism. Nat Rev Cancer 9:691–700

    CAS  PubMed  Google Scholar 

  10. Sutendra G, Dromparis P, Kinnaird A, Stenson TH, Haromy A, Parker JM, McMurtry MS, Michelakis ED (2012) Mitochondrial activation by inhibition of PDKII suppresses HIF1a signaling and angiogenesis in cancer. Oncogene 32:1638–1650

    PubMed  Google Scholar 

  11. Maddocks OD, Vousden KH (2011) Metabolic regulation by p53. J Mol Med (Berl) 89:237–245

    CAS  Google Scholar 

  12. Dromparis P, Michelakis ED (2013) Mitochondria in vascular health and disease. Annu Rev Physiol 75:95–126

    CAS  PubMed  Google Scholar 

  13. Sutendra G, Michelakis ED (2013) Pyruvate dehydrogenase kinase as a novel therapeutic target in oncology. Front Oncol 3:38

    PubMed Central  PubMed  Google Scholar 

  14. Zamzami N, Kroemer G (2001) The mitochondrion in apoptosis: how Pandora's box opens. Nat Rev Mol Cell Biol 2:67–71

    CAS  PubMed  Google Scholar 

  15. Chen LB (1988) Mitochondrial membrane potential in living cells. Annu Rev Cell Biol 4:155–181

    CAS  PubMed  Google Scholar 

  16. Lemasters JJ, Holmuhamedov E (2006) Voltage-dependent anion channel (VDAC) as mitochondrial governator—thinking outside the box. Biochim Biophys Acta 1762:181–190

    CAS  PubMed  Google Scholar 

  17. 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

    CAS  PubMed  Google Scholar 

  18. Vander Heiden MG, Cantley LC, Thompson CB (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324:1029–1033

    CAS  PubMed Central  PubMed  Google Scholar 

  19. Butow RA, Avadhani NG (2004) Mitochondrial signaling: the retrograde response. Mol Cell 14:1–15

    CAS  PubMed  Google Scholar 

  20. Esteves P, Pecqueur C, Ransy C, Esnous C, Lenoir V, Bouillaud F, Bulteau AL, Lombes A, Prip-Buus C, Ricquier D et al (2014) Mitochondrial retrograde signaling mediated by UCP2 inhibits cancer cell proliferation and tumorigenesis. Cancer Res 74:3971–3982

    CAS  PubMed  Google Scholar 

  21. Wallace DC (2012) Mitochondria and cancer. Nat Rev Cancer 12:685–698

    CAS  PubMed  Google Scholar 

  22. Semenza GL (2010) HIF-1: upstream and downstream of cancer metabolism. Curr Opin Genet Dev 20:51–56

    CAS  PubMed Central  PubMed  Google Scholar 

  23. Denko NC (2008) Hypoxia, HIF1 and glucose metabolism in the solid tumour. Nat Rev Cancer 8:705–713

    CAS  PubMed  Google Scholar 

  24. Yu F, White SB, Zhao Q, Lee FS (2001) HIF-1alpha binding to VHL is regulated by stimulus-sensitive proline hydroxylation. Proc Natl Acad Sci U S A 98:9630–9635

    CAS  PubMed Central  PubMed  Google Scholar 

  25. Ke Q, Costa M (2006) Hypoxia-inducible factor-1 (HIF-1). Mol Pharmacol 70:1469–1480

    CAS  PubMed  Google Scholar 

  26. Gatenby RA, Gillies RJ (2004) Why do cancers have high aerobic glycolysis? Nat Rev Cancer 4:891–899

    CAS  PubMed  Google Scholar 

  27. Hitosugi T, Fan J, Chung TW, Lythgoe K, Wang X, Xie J, Ge Q, Gu TL, Polakiewicz RD, Roesel JL et al (2011) Tyrosine phosphorylation of mitochondrial pyruvate dehydrogenase kinase 1 is important for cancer metabolism. Mol Cell 44:864–877

    CAS  PubMed Central  PubMed  Google Scholar 

  28. Korotchkina LG, Patel MS (2001) Probing the mechanism of inactivation of human pyruvate dehydrogenase by phosphorylation of three sites. J Biol Chem 276:5731–5738

    CAS  PubMed  Google Scholar 

  29. Fan J, Kang HB, Shan C, Elf S, Lin R, Xie J, Gu TL, Aguiar M, Lonning S, Chung TW et al (2014) Tyr-301 phosphorylation inhibits pyruvate dehydrogenase by blocking substrate binding and promotes the Warburg effect. J Biol Chem 289:26533–26541

    CAS  PubMed  Google Scholar 

  30. Kim JW, Tchernyshyov I, Semenza GL, Dang CV (2006) HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab 3:177–185

    PubMed  Google Scholar 

  31. Franovic A, Gunaratnam L, Smith K, Robert I, Patten D, Lee S (2007) Translational up-regulation of the EGFR by tumor hypoxia provides a nonmutational explanation for its overexpression in human cancer. Proc Natl Acad Sci U S A 104:13092–13097

    CAS  PubMed Central  PubMed  Google Scholar 

  32. Wu P, Inskeep K, Bowker-Kinley MM, Popov KM, Harris RA (1999) Mechanism responsible for inactivation of skeletal muscle pyruvate dehydrogenase complex in starvation and diabetes. Diabetes 48:1593–1599

    CAS  PubMed  Google Scholar 

  33. Kandoth C, McLellan MD, Vandin F, Ye K, Niu B, Lu C, Xie M, Zhang Q, McMichael JF, Wyczalkowski MA et al (2013) Mutational landscape and significance across 12 major cancer types. Nature 502:333–339

    CAS  PubMed Central  PubMed  Google Scholar 

  34. 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

    CAS  PubMed  Google Scholar 

  35. 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

    CAS  PubMed  Google Scholar 

  36. 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

    CAS  PubMed  Google Scholar 

  37. Contractor T, Harris CR (2012) p53 negatively regulates transcription of the pyruvate dehydrogenase kinase Pdk2. Cancer Res 72:560–567

    CAS  PubMed  Google Scholar 

  38. Mathupala SP, Heese C, Pedersen PL (1997) Glucose catabolism in cancer cells. The type II hexokinase promoter contains functionally active response elements for the tumor suppressor p53. J Biol Chem 272:22776–22780

    CAS  PubMed  Google Scholar 

  39. Choudhary C, Weinert BT, Nishida Y, Verdin E, Mann M (2014) The growing landscape of lysine acetylation links metabolism and cell signalling. Nat Rev Mol Cell Biol 15:536–550

    CAS  PubMed  Google Scholar 

  40. Dang CV, Semenza GL (1999) Oncogenic alterations of metabolism. Trends Biochem Sci 24:68–72

    CAS  PubMed  Google Scholar 

  41. 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 U S A 94:6658–6663

    CAS  PubMed Central  PubMed  Google Scholar 

  42. 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

    CAS  PubMed Central  PubMed  Google Scholar 

  43. Nogueiras R, Habegger KM, Chaudhary N, Finan B, Banks AS, Dietrich MO, Horvath TL, Sinclair DA, Pfluger PT, Tschop MH (2012) Sirtuin 1 and sirtuin 3: physiological modulators of metabolism. Physiol Rev 92:1479–1514

    CAS  PubMed Central  PubMed  Google Scholar 

  44. He W, Newman JC, Wang MZ, Ho L, Verdin E (2012) Mitochondrial sirtuins: regulators of protein acylation and metabolism. Trends Endocrinol Metab: TEM 23:467–476

    CAS  PubMed  Google Scholar 

  45. Kim HS, Patel K, Muldoon-Jacobs K, Bisht KS, Aykin-Burns N, Pennington JD, van der Meer R, Nguyen P, Savage J, Owens KM et al (2010) SIRT3 is a mitochondria-localized tumor suppressor required for maintenance of mitochondrial integrity and metabolism during stress. Cancer Cell 17:41–52

    CAS  PubMed Central  PubMed  Google Scholar 

  46. Guarente L (2014) The many faces of Sirtuins: Sirtuins and the Warburg effect. Nat Med 20:24–25

    CAS  PubMed  Google Scholar 

  47. Finley LW, Carracedo A, Lee J, Souza A, Egia A, Zhang J, Teruya-Feldstein J, Moreira PI, Cardoso SM, Clish CB et al (2011) SIRT3 opposes reprogramming of cancer cell metabolism through HIF1alpha destabilization. Cancer Cell 19:416–428

    CAS  PubMed Central  PubMed  Google Scholar 

  48. Denton RM (2009) Regulation of mitochondrial dehydrogenases by calcium ions. Biochim Biophys Acta 1787:1309–1316

    CAS  PubMed  Google Scholar 

  49. Dromparis P, Paulin R, Sutendra G, Qi AC, Bonnet S, Michelakis ED (2013) Uncoupling protein 2 deficiency mimics the effects of hypoxia and endoplasmic reticulum stress on mitochondria and triggers pseudohypoxic pulmonary vascular remodeling and pulmonary hypertension. Circ Res 113:126–136

    CAS  PubMed  Google Scholar 

  50. Derdak Z, Fulop P, Sabo E, Tavares R, Berthiaume EP, Resnick MB, Paragh G, Wands JR, Baffy G (2006) Enhanced colon tumor induction in uncoupling protein-2 deficient mice is associated with NF-kappaB activation and oxidative stress. Carcinogenesis 27:956–961

    CAS  PubMed  Google Scholar 

  51. Archer SL (2013) Mitochondrial dynamics–mitochondrial fission and fusion in human diseases. N Engl J Med 369:2236–2251

    CAS  PubMed  Google Scholar 

  52. Mitra K, Wunder C, Roysam B, Lin G, Lippincott-Schwartz J (2009) A hyperfused mitochondrial state achieved at G1-S regulates cyclin E buildup and entry into S phase. Proc Natl Acad Sci U S A 106:11960–11965

    CAS  PubMed Central  PubMed  Google Scholar 

  53. Rehman J, Zhang HJ, Toth PT, Zhang Y, Marsboom G, Hong Z, Salgia R, Husain AN, Wietholt C, Archer SL (2012) Inhibition of mitochondrial fission prevents cell cycle progression in lung cancer. FASEB J: Off Publ Fed Am Soc Exp Biol 26:2175–2186

    CAS  Google Scholar 

  54. 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

    CAS  PubMed  Google Scholar 

  55. Neumann HP, Pawlu C, Peczkowska M, Bausch B, McWhinney SR, Muresan M, Buchta M, Franke G, Klisch J, Bley TA et al (2004) Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. Jama 292:943–951

    CAS  PubMed  Google Scholar 

  56. Baysal BE (2003) On the association of succinate dehydrogenase mutations with hereditary paraganglioma. Trends Endocrinol Metab: TEM 14:453–459

    CAS  PubMed  Google Scholar 

  57. 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

    CAS  PubMed  Google Scholar 

  58. King A, Selak MA, Gottlieb E (2006) Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer. Oncogene 25:4675–4682

    CAS  PubMed  Google Scholar 

  59. 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

    CAS  PubMed  Google Scholar 

  60. Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Siu IM, Gallia GL et al (2008) An integrated genomic analysis of human glioblastoma multiforme. Science 321:1807–1812

    CAS  PubMed Central  PubMed  Google Scholar 

  61. Mardis ER, Ding L, Dooling DJ, Larson DE, McLellan MD, Chen K, Koboldt DC, Fulton RS, Delehaunty KD, McGrath SD et al (2009) Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med 361:1058–1066

    CAS  PubMed Central  PubMed  Google Scholar 

  62. Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM, Fantin VR, Jang HG, Jin S, Keenan MC et al (2009) Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462:739–744

    CAS  PubMed Central  PubMed  Google Scholar 

  63. Ward PS, Patel J, Wise DR, Abdel-Wahab O, Bennett BD, Coller HA, Cross JR, Fantin VR, Hedvat CV, Perl AE et al (2010) The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 17:225–234

    CAS  PubMed Central  PubMed  Google Scholar 

  64. Rose NR, McDonough MA, King ON, Kawamura A, Schofield CJ (2011) Inhibition of 2-oxoglutarate dependent oxygenases. Chem Soc Rev 40:4364–4397

    CAS  PubMed  Google Scholar 

  65. Guan KL, Xiong Y (2011) Regulation of intermediary metabolism by protein acetylation. Trends Biochem Sci 36:108–116

    CAS  PubMed Central  PubMed  Google Scholar 

  66. Zhao S, Xu W, Jiang W, Yu W, Lin Y, Zhang T, Yao J, Zhou L, Zeng Y, Li H et al (2010) Regulation of cellular metabolism by protein lysine acetylation. Science 327:1000–1004

    CAS  PubMed Central  PubMed  Google Scholar 

  67. Devi MA, Das NP (1993) In vitro effects of natural plant polyphenols on the proliferation of normal and abnormal human lymphocytes and their secretions of interleukin-2. Cancer Lett 69:191–196

    CAS  PubMed  Google Scholar 

  68. Kobori M, Shinmoto H, Tsushida T, Shinohara K (1997) Phloretin-induced apoptosis in B16 melanoma 4A5 cells by inhibition of glucose transmembrane transport. Cancer Lett 119:207–212

    CAS  PubMed  Google Scholar 

  69. Porporato PE, Dhup S, Dadhich RK, Copetti T, Sonveaux P (2011) Anticancer targets in the glycolytic metabolism of tumors: a comprehensive review. Front Pharmacol 2:49

    PubMed Central  PubMed  Google Scholar 

  70. Tennant DA, Duran RV, Gottlieb E (2010) Targeting metabolic transformation for cancer therapy. Nat Rev Cancer 10:267–277

    CAS  PubMed  Google Scholar 

  71. Ko YH, Verhoeven HA, Lee MJ, Corbin DJ, Vogl TJ, Pedersen PL (2012) A translational study “case report” on the small molecule “energy blocker” 3-bromopyruvate (3BP) as a potent anticancer agent: from bench side to bedside. J Bioenerg Biomembr 44:163–170

    CAS  PubMed  Google Scholar 

  72. Ko YH, Smith BL, Wang Y, Pomper MG, Rini DA, Torbenson MS, Hullihen J, Pedersen PL (2004) Advanced cancers: eradication in all cases using 3-bromopyruvate therapy to deplete ATP. Biochem Biophys Res Commun 324:269–275

    CAS  PubMed  Google Scholar 

  73. Biolato M, Marrone G, Racco S, Di Stasi C, Miele L, Gasbarrini G, Landolfi R, Grieco A (2010) Transarterial chemoembolization (TACE) for unresectable HCC: a new life begins? Eur Rev Med Pharmacol Sci 14:356–362

    CAS  PubMed  Google Scholar 

  74. DeBerardinis RJ, Mancuso A, Daikhin E, Nissim I, Yudkoff M, Wehrli S, Thompson CB (2007) Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc Natl Acad Sci U S A 104:19345–19350

    CAS  PubMed Central  PubMed  Google Scholar 

  75. Hutson SM, Sweatt AJ, Lanoue KF (2005) Branched-chain [corrected] amino acid metabolism: implications for establishing safe intakes. J Nutr 135:1557S–1564S

    CAS  PubMed  Google Scholar 

  76. Gupta V, Bamezai RN (2010) Human pyruvate kinase M2: a multifunctional protein. Protein Sci 19:2031–2044

    CAS  PubMed Central  PubMed  Google Scholar 

  77. Takenaka M, Noguchi T, Sadahiro S, Hirai H, Yamada K, Matsuda T, Imai E, Tanaka T (1991) Isolation and characterization of the human pyruvate kinase M gene. Eur J Biochem 198:101–106

    CAS  PubMed  Google Scholar 

  78. Noguchi T, Inoue H, Tanaka T (1986) The M1- and M2-type isozymes of rat pyruvate kinase are produced from the same gene by alternative RNA splicing. J Biol Chem 261:13807–13812

    CAS  PubMed  Google Scholar 

  79. Munoz ME, Ponce E (2003) Pyruvate kinase: current status of regulatory and functional properties. Comp Biochem Physiol B Biochem Mol Biol 135:197–218

    PubMed  Google Scholar 

  80. Wong N, De Melo J, Tang D (2013) PKM2, a central point of regulation in cancer metabolism. Int J Cell Biol 2013:242513

    PubMed Central  PubMed  Google Scholar 

  81. Imamura K, Tanaka T (1972) Multimolecular forms of pyruvate kinase from rat and other mammalian tissues. I electrophoretic studies. J Biochem 71:1043–1051

    CAS  PubMed  Google Scholar 

  82. Mazurek S (2011) Pyruvate kinase type M2: a key regulator of the metabolic budget system in tumor cells. Int J Biochem Cell Biol 43:969–980

    CAS  PubMed  Google Scholar 

  83. Anastasiou D, Yu Y, Israelsen WJ, Jiang JK, Boxer MB, Hong BS, Tempel W, Dimov S, Shen M, Jha A et al (2012) Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis. Nat Chem Biol 8:839–847

    CAS  PubMed Central  PubMed  Google Scholar 

  84. Christofk HR, Vander Heiden MG, Harris MH, Ramanathan A, Gerszten RE, Wei R, Fleming MD, Schreiber SL, Cantley LC (2008) The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature 452:230–233

    CAS  PubMed  Google Scholar 

  85. Lv L, Li D, Zhao D, Lin R, Chu Y, Zhang H, Zha Z, Liu Y, Li Z, Xu Y et al (2011) Acetylation targets the M2 isoform of pyruvate kinase for degradation through chaperone-mediated autophagy and promotes tumor growth. Mol Cell 42:719–730

    CAS  PubMed  Google Scholar 

  86. Hitosugi T, Kang S, Vander Heiden MG, Chung TW, Elf S, Lythgoe K, Dong S, Lonial S, Wang X, et al (2009) Tyrosine phosphorylation inhibits PKM2 to promote the Warburg effect and tumor growth. Sci Signal 2: ra73

  87. Christofk HR, Vander Heiden MG, Wu N, Asara JM, Cantley LC (2008) Pyruvate kinase M2 is a phosphotyrosine-binding protein. Nature 452:181–186

    CAS  PubMed  Google Scholar 

  88. Ashizawa K, Willingham MC, Liang CM, Cheng SY (1991) In vivo regulation of monomer-tetramer conversion of pyruvate kinase subtype M2 by glucose is mediated via fructose 1,6-bisphosphate. J Biol Chem 266:16842–16846

    CAS  PubMed  Google Scholar 

  89. Israelsen WJ, Dayton TL, Davidson SM, Fiske BP, Hosios AM, Bellinger G, Li J, Yu Y, Sasaki M, Horner JW et al (2013) PKM2 isoform-specific deletion reveals a differential requirement for pyruvate kinase in tumor cells. Cell 155:397–409

    CAS  PubMed  Google Scholar 

  90. Walsh MJ, Brimacombe KR, Anastasiou D, Yu Y, Israelsen WJ, Hong BS, Tempel W, Dimov S, Veith H, Yang H, et al (2010) ML265: A potent PKM2 activator induces tetramerization and reduces tumor formation and size in a mouse xenograft modelProbe Reports from the NIH Molecular Libraries Program, Bethesda (MD)

  91. Parnell KM, Foulks JM, Nix RN, Clifford A, Bullough J, Luo B, Senina A, Vollmer D, Liu J, McCarthy V et al (2013) Pharmacologic activation of PKM2 slows lung tumor xenograft growth. Mol Cancer Ther 12:1453–1460

    CAS  PubMed  Google Scholar 

  92. Michelakis ED, Webster L, Mackey JR (2008) Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer. Br J Cancer 99:989–994

    CAS  PubMed Central  PubMed  Google Scholar 

  93. Sutendra G, Michelakis ED (2014) The metabolic basis of pulmonary arterial hypertension. Cell Metab 19:558–573

    CAS  PubMed  Google Scholar 

  94. Michelakis ED, Sutendra G, Dromparis P, Webster L, Haromy A, Niven E, Maguire C, Gammer TL, Mackey JR, Fulton D, et al (2010) Metabolic modulation of glioblastoma with dichloroacetate. Sci Transl Med 2: 31ra34

  95. Bowker-Kinley MM, Davis WI, Wu P, Harris RA, Popov KM (1998) Evidence for existence of tissue-specific regulation of the mammalian pyruvate dehydrogenase complex. Biochem J 329(Pt 1):191–196

    CAS  PubMed Central  PubMed  Google Scholar 

  96. Stacpoole PW (1989) The pharmacology of dichloroacetate. Metabolism 38:1124–1144

    CAS  PubMed  Google Scholar 

  97. Bonnet S, Archer SL, Allalunis-Turner J, Haromy A, Beaulieu C, Thompson R, Lee CT, Lopaschuk GD, Puttagunta L, Harry G 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

    CAS  PubMed  Google Scholar 

  98. Stacpoole PW, Moore GW, Kornhauser DM (1978) Metabolic effects of dichloroacetate in patients with diabetes mellitus and hyperlipoproteinemia. N Engl J Med 298:526–530

    CAS  PubMed  Google Scholar 

  99. Stacpoole PW, Wright EC, Baumgartner TG, Bersin RM, Buchalter S, Curry SH, Duncan CA, Harman EM, Henderson GN, Jenkinson S et al (1992) A controlled clinical trial of dichloroacetate for treatment of lactic acidosis in adults. The Dichloroacetate-Lactic Acidosis Study Group. N Engl J Med 327:1564–1569

    CAS  PubMed  Google Scholar 

  100. Stacpoole PW, Kerr DS, Barnes C, Bunch ST, Carney PR, Fennell EM, Felitsyn NM, Gilmore RL, Greer M, Henderson GN et al (2006) Controlled clinical trial of dichloroacetate for treatment of congenital lactic acidosis in children. Pediatrics 117:1519–1531

    PubMed  Google Scholar 

  101. McMurtry MS, Bonnet S, Wu X, Dyck JR, Haromy A, Hashimoto K, Michelakis ED (2004) Dichloroacetate prevents and reverses pulmonary hypertension by inducing pulmonary artery smooth muscle cell apoptosis. Circ Res 95:830–840

    CAS  PubMed  Google Scholar 

  102. Krishna S, Supanaranond W, Pukrittayakamee S, Kuile FT, Ruprah M, White NJ (1996) The disposition and effects of two doses of dichloroacetate in adults with severe falciparum malaria. Br J Clin Pharmacol 41:29–34

    CAS  PubMed  Google Scholar 

  103. Bersin RM, Wolfe C, Kwasman M, Lau D, Klinski C, Tanaka K, Khorrami P, Henderson GN, de Marco T, Chatterjee K (1994) Improved hemodynamic function and mechanical efficiency in congestive heart failure with sodium dichloroacetate. J Am Coll Cardiol 23:1617–1624

    CAS  PubMed  Google Scholar 

  104. Calvert LD, Shelley R, Singh SJ, Greenhaff PL, Bankart J, Morgan MD, Steiner MC (2008) Dichloroacetate enhances performance and reduces blood lactate during maximal cycle exercise in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 177:1090–1094

    CAS  PubMed  Google Scholar 

  105. Stacpoole PW (1969) Review of the pharmacologic and therapeutic effects of diisopropylammonium dichloroacetate (DIPA). J Clin Pharmacol J New Drugs 9:282–291

    CAS  PubMed  Google Scholar 

  106. Holloway PA, Knox K, Bajaj N, Chapman D, White NJ, O'Brien R, Stacpoole PW, Krishna S (1995) Plasmodium berghei infection: dichloroacetate improves survival in rats with lactic acidosis. Exp Parasitol 80:624–632

    CAS  PubMed  Google Scholar 

  107. 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

    CAS  PubMed  Google Scholar 

  108. Sanchez-Arago M, Chamorro M, Cuezva JM (2010) Selection of cancer cells with repressed mitochondria triggers colon cancer progression. Carcinogenesis 31:567–576

    CAS  PubMed  Google Scholar 

  109. Madhok BM, Yeluri S, Perry SL, Hughes TA, Jayne DG (2010) Dichloroacetate induces apoptosis and cell-cycle arrest in colorectal cancer cells. Br J Cancer 102:1746–1752

    CAS  PubMed Central  PubMed  Google Scholar 

  110. Sebastian C, Zwaans BM, Silberman DM, Gymrek M, Goren A, Zhong L, Ram O, Truelove J, Guimaraes AR, Toiber D et al (2012) The histone deacetylase SIRT6 is a tumor suppressor that controls cancer metabolism. Cell 151:1185–1199

    CAS  PubMed Central  PubMed  Google Scholar 

  111. Xuan Y, Hur H, Ham IH, Yun J, Lee JY, Shim W, Bae Kim Y, Lee G, Han SU, Kwan Cho Y (2013) Dichloroacetate attenuates hypoxia-induced resistance to 5-fluorouracil in gastric cancer through the regulation of glucose metabolism. Exp Cell Res 321(2):219–230

    PubMed  Google Scholar 

  112. Wong JY, Huggins GS, Debidda M, Munshi NC, De Vivo I (2008) Dichloroacetate induces apoptosis in endometrial cancer cells. Gynecol Oncol 109:394–402

    CAS  PubMed Central  PubMed  Google Scholar 

  113. Kumar K, Wigfield S, Gee HE, Devlin CM, Singleton D, Li JL, Buffa F, Huffman M, Sinn AL, Silver J et al (2013) Dichloroacetate reverses the hypoxic adaptation to bevacizumab and enhances its antitumor effects in mouse xenografts. J Mol Med (Berl) 91:749–758

    CAS  Google Scholar 

  114. Vella S, Conti M, Tasso R, Cancedda R, Pagano A (2012) Dichloroacetate inhibits neuroblastoma growth by specifically acting against malignant undifferentiated cells. Int J Cancer 130:1484–1493

    CAS  PubMed  Google Scholar 

  115. Kumar A, Kant S, Singh SM (2012) Novel molecular mechanisms of antitumor action of dichloroacetate against T cell lymphoma: Implication of altered glucose metabolism, pH homeostasis and cell survival regulation. Chem Biol Interact 199:29–37

    CAS  PubMed  Google Scholar 

  116. Flavin DF (2010) Non-Hodgkin’s lymphoma reversal with dichloroacetate. J Oncol 2010

  117. Ishiguro T, Ishiguro R, Ishiguro M, Iwai S (2012) Co-treatment of dichloroacetate, omeprazole and tamoxifen exhibited synergistically antiproliferative effect on malignant tumors: in vivo experiments and a case report. Hepatogastroenterology 59:994–996

    CAS  PubMed  Google Scholar 

  118. Sun RC, Fadia M, Dahlstrom JE, Parish CR, Board PG, Blackburn AC (2010) Reversal of the glycolytic phenotype by dichloroacetate inhibits metastatic breast cancer cell growth in vitro and in vivo. Breast Cancer Res Treat 120:253–260

    CAS  PubMed  Google Scholar 

  119. Kaluzova M, Kaluz S, Lerman MI, Stanbridge EJ (2004) DNA damage is a prerequisite for p53-mediated proteasomal degradation of HIF-1alpha in hypoxic cells and downregulation of the hypoxia marker carbonic anhydrase IX. Mol Cell Biol 24:5757–5766

    CAS  PubMed Central  PubMed  Google Scholar 

  120. Kaplon J, Zheng L, Meissl K, Chaneton B, Selivanov VA, Mackay G, van der Burg SH, Verdegaal EM, Cascante M, Shlomi T et al (2013) A key role for mitochondrial gatekeeper pyruvate dehydrogenase in oncogene-induced senescence. Nature 498:109–112

    CAS  PubMed  Google Scholar 

  121. Dunbar EM, Coats BS, Shroads AL, Langaee T, Lew A, Forder JR, Shuster JJ, Wagner DA, Stacpoole PW (2013) Phase 1 trial of dichloroacetate (DCA) in adults with recurrent malignant brain tumors. Invest New Drugs 32(2):452–464

    PubMed  Google Scholar 

  122. Abdelmalak M, Lew A, Ramezani R, Shroads AL, Coats BS, Langaee T, Shankar MN, Neiberger RE, Subramony SH, Stacpoole PW (2013) Long-term safety of dichloroacetate in congenital lactic acidosis. Mol Genet Metab 109:139–143

    CAS  PubMed Central  PubMed  Google Scholar 

  123. Dhar S, Lippard SJ (2009) Mitaplatin, a potent fusion of cisplatin and the orphan drug dichloroacetate. Proc Natl Acad Sci U S A 106:22199–22204

    CAS  PubMed Central  PubMed  Google Scholar 

  124. Morfouace M, Lalier L, Bahut M, Bonnamain V, Naveilhan P, Guette C, Oliver L, Gueguen N, Reynier P, Vallette FM (2012) Comparison of spheroids formed by rat glioma stem cells and neural stem cells reveals differences in glucose metabolism and promising therapeutic applications. J Biol Chem 287:33664–33674

    CAS  PubMed Central  PubMed  Google Scholar 

  125. Markert CL, Shaklee JB, Whitt GS (1975) Evolution of a gene. Multiple genes for LDH isozymes provide a model of the evolution of gene structure, function and regulation. Science 189:102–114

    CAS  PubMed  Google Scholar 

  126. Koukourakis MI, Giatromanolaki A, Sivridis E, Bougioukas G, Didilis V, Gatter KC, Harris AL (2003) Lactate dehydrogenase-5 (LDH-5) overexpression in non-small-cell lung cancer tissues is linked to tumour hypoxia, angiogenic factor production and poor prognosis. Br J Cancer 89:877–885

    CAS  PubMed Central  PubMed  Google Scholar 

  127. Leiblich A, Cross SS, Catto JW, Phillips JT, Leung HY, Hamdy FC, Rehman I (2006) Lactate dehydrogenase-B is silenced by promoter hypermethylation in human prostate cancer. Oncogene 25:2953–2960

    CAS  PubMed  Google Scholar 

  128. Koukourakis MI, Giatromanolaki A, Sivridis E, Gatter KC, Trarbach T, Folprecht G, Shi MM, Lebwohl D, Jalava T, Laurent D et al (2011) Prognostic and predictive role of lactate dehydrogenase 5 expression in colorectal cancer patients treated with PTK787/ZK 222584 (vatalanib) antiangiogenic therapy. Clin Cancer Res 17:4892–4900

    CAS  PubMed Central  PubMed  Google Scholar 

  129. Koukourakis MI, Giatromanolaki A, Winter S, Leek R, Sivridis E, Harris AL (2009) Lactate dehydrogenase 5 expression in squamous cell head and neck cancer relates to prognosis following radical or postoperative radiotherapy. Oncology 77:285–292

    CAS  PubMed  Google Scholar 

  130. 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

    CAS  PubMed  Google Scholar 

  131. Le A, Cooper CR, Gouw AM, Dinavahi R, Maitra A, Deck LM, Royer RE, Vander Jagt DL, Semenza GL, Dang CV (2010) Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression. Proc Natl Acad Sci U S A 107:2037–2042

    CAS  PubMed Central  PubMed  Google Scholar 

  132. Granchi C, Roy S, Giacomelli C, Macchia M, Tuccinardi T, Martinelli A, Lanza M, Betti L, Giannaccini G, Lucacchini A et al (2011) Discovery of N-hydroxyindole-based inhibitors of human lactate dehydrogenase isoform A (LDH-A) as starvation agents against cancer cells. J Med Chem 54:1599–1612

    CAS  PubMed  Google Scholar 

  133. Maftouh M, Avan A, Sciarrillo R, Granchi C, Leon LG, Rani R, Funel N, Smid K, Honeywell R, Boggi U et al (2014) Synergistic interaction of novel lactate dehydrogenase inhibitors with gemcitabine against pancreatic cancer cells in hypoxia. Br J Cancer 110(1):172–182

    CAS  PubMed Central  PubMed  Google Scholar 

  134. Golman K, Zandt RI, Lerche M, Pehrson R, Ardenkjaer-Larsen JH (2006) Metabolic imaging by hyperpolarized 13C magnetic resonance imaging for in vivo tumor diagnosis. Cancer Res 66:10855–10860

    CAS  PubMed  Google Scholar 

  135. Dutta P, Le A, Vander Jagt DL, Tsukamoto T, Martinez GV, Dang CV, Gillies RJ (2013) Evaluation of LDH-A and glutaminase inhibition in vivo by hyperpolarized 13C-pyruvate magnetic resonance spectroscopy of tumors. Cancer Res 73:4190–4195

    CAS  PubMed Central  PubMed  Google Scholar 

  136. Hill DK, Orton MR, Mariotti E, Boult JK, Panek R, Jafar M, Parkes HG, Jamin Y, Miniotis MF, Al-Saffar NM et al (2013) Model free approach to kinetic analysis of real-time hyperpolarized 13C magnetic resonance spectroscopy data. PLoS One 8:e71996

    CAS  PubMed Central  PubMed  Google Scholar 

  137. Wang F, Travins J, DeLaBarre B, Penard-Lacronique V, Schalm S, Hansen E, Straley K, Kernytsky A, Liu W, Gliser C et al (2013) Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation. Science 340:622–626

    CAS  PubMed  Google Scholar 

  138. Rohle D, Popovici-Muller J, Palaskas N, Turcan S, Grommes C, Campos C, Tsoi J, Clark O, Oldrini B, Komisopoulou E et al (2013) An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells. Science 340:626–630

    CAS  PubMed Central  PubMed  Google Scholar 

  139. Fathi AT, Sadrzadeh H, Borger DR, Ballen KK, Amrein PC, Attar EC, Foster J, Burke M, Lopez HU, Matulis CR et al (2012) Prospective serial evaluation of 2-hydroxyglutarate, during treatment of newly diagnosed acute myeloid leukemia, to assess disease activity and therapeutic response. Blood 120:4649–4652

    CAS  PubMed  Google Scholar 

  140. Folmes CD, Nelson TJ, Martinez-Fernandez A, Arrell DK, Lindor JZ, Dzeja PP, Ikeda Y, Perez-Terzic C, Terzic A (2011) Somatic oxidative bioenergetics transitions into pluripotency-dependent glycolysis to facilitate nuclear reprogramming. Cell Metab 14:264–271

    CAS  PubMed Central  PubMed  Google Scholar 

  141. Xu X, Duan S, Yi F, Ocampo A, Liu GH, Izpisua Belmonte JC (2013) Mitochondrial regulation in pluripotent stem cells. Cell Metab 18:325–332

    CAS  PubMed  Google Scholar 

  142. Varum S, Rodrigues AS, Moura MB, Momcilovic O, Easley CA, Ramalho-Santos J, Van Houten B, Schatten G (2011) Energy metabolism in human pluripotent stem cells and their differentiated counterparts. PLoS One 6:e20914

    CAS  PubMed Central  PubMed  Google Scholar 

  143. Ye XQ, Li Q, Wang GH, Sun FF, Huang GJ, Bian XW, Yu SC, Qian GS (2011) Mitochondrial and energy metabolism-related properties as novel indicators of lung cancer stem cells. Int J Cancer 129:820–831

    CAS  PubMed  Google Scholar 

  144. Vega-Naredo I, Loureiro R, Mesquita KA, Barbosa IA, Tavares LC, Branco AF, Erickson JR, Holy J, Perkins EL, Carvalho RA et al (2014) Mitochondrial metabolism directs stemness and differentiation in P19 embryonal carcinoma stem cells. Cell Death Differ 21:1560–1574

    CAS  PubMed  Google Scholar 

  145. Figueroa ME, Abdel-Wahab O, Lu C, Ward PS, Patel J, Shih A, Li Y, Bhagwat N, Vasanthakumar A, Fernandez HF et al (2010) Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 18:553–567

    CAS  PubMed Central  PubMed  Google Scholar 

  146. Minucci S, Pelicci PG (2006) Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer 6:38–51

    CAS  PubMed  Google Scholar 

  147. Lee JV, Carrer A, Shah S, Snyder NW, Wei S, Venneti S, Worth AJ, Yuan ZF, Lim HW, Liu S et al (2014) Akt-dependent metabolic reprogramming regulates tumor cell histone acetylation. Cell Metab 20(2):306–319

    CAS  PubMed  Google Scholar 

  148. Wellen KE, Hatzivassiliou G, Sachdeva UM, Bui TV, Cross JR, Thompson CB (2009) ATP-citrate lyase links cellular metabolism to histone acetylation. Science 324:1076–1080

    CAS  PubMed Central  PubMed  Google Scholar 

  149. Mullen AR, Wheaton WW, Jin ES, Chen PH, Sullivan LB, Cheng T, Yang Y, Linehan WM, Chandel NS, DeBerardinis RJ (2012) Reductive carboxylation supports growth in tumour cells with defective mitochondria. Nature 481:385–388

    CAS  Google Scholar 

  150. Sutendra G, Kinnaird A, Dromparis P, Paulin R, Stenson TH, Haromy A, Hashimoto K, Zhang N, Flaim E, Michelakis ED (2014) A nuclear pyruvate dehydrogenase complex is important for the generation of acetyl-CoA and histone acetylation. Cell 158:84–97

    CAS  PubMed  Google Scholar 

  151. Chueh FY, Leong KF, Cronk RJ, Venkitachalam S, Pabich S, Yu CL (2011) Nuclear localization of pyruvate dehydrogenase complex-E2 (PDC-E2), a mitochondrial enzyme, and its role in signal transducer and activator of transcription 5 (STAT5)-dependent gene transcription. Cell Signal 23:1170–1178

    CAS  PubMed Central  PubMed  Google Scholar 

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Funding

Adam Kinnaird is a Vanier Scholar supported by the Canadian Institutes of Health Research (CIHR). Evangelos Michelakis is supported by CIHR and the Canada Research Chair Program.

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  1. Department of Medicine, University of Alberta, Edmonton, AB, T6G 2B7, Canada

    Adam Kinnaird & Evangelos D. Michelakis

  2. Division of Urology, University of Alberta, Edmonton, AB, T6G 2B7, Canada

    Adam Kinnaird

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  1. Adam Kinnaird
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Correspondence to Evangelos D. Michelakis.

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Kinnaird, A., Michelakis, E.D. Metabolic modulation of cancer: a new frontier with great translational potential. J Mol Med 93, 127–142 (2015). https://doi.org/10.1007/s00109-014-1250-2

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