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Metabolic rewiring in melanoma

Oncogene volume 36, pages 147–157 (2017)Cite this article

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Abstract

Oncogene-driven metabolic rewiring is an adaptation to low nutrient and oxygen conditions in the tumor microenvironment that enables cancer cells of diverse origin to hyperproliferate. Aerobic glycolysis and enhanced reliance on glutamine utilization are prime examples of such rewiring. However, tissue of origin as well as specific genetic and epigenetic changes determines gene expression profiles underlying these metabolic alterations in specific cancers. In melanoma, activation of the mitogen-activated protein kinase (MAPK) pathway driven by mutant BRAF or NRAS is a primary cause of malignant transformation. Activity of the MAPK pathway, as well as other factors, such as HIF1α, Myc and MITF, are among those that control the balance between non-oxidative and oxidative branches of central carbon metabolism. Here, we discuss the nature of metabolic alterations that underlie melanoma development and affect its response to therapy.

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References

  1. Lo JA, Fisher DE . The melanoma revolution: from UV carcinogenesis to a new era in therapeutics. Science 2014; 346: 945–949.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Cancer Genome Atlas N. Genomic classification of cutaneous melanoma. Cell 2015; 161: 1681–1696.

    Google Scholar 

  3. Lin JY, Fisher DE . Melanocyte biology and skin pigmentation. Nature 2007; 445: 843–850.

    CAS  PubMed  Google Scholar 

  4. Van Raamsdonk CD, Bezrookove V, Green G, Bauer J, Gaugler L, O'Brien JM et al. Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature 2009; 457: 599–602.

    CAS  PubMed  Google Scholar 

  5. Van Raamsdonk CD, Griewank KG, Crosby MB, Garrido MC, Vemula S, Wiesner T et al. Mutations in GNA11 in uveal melanoma. N Engl J Med 2010; 363: 2191–2199.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Boroughs LK, DeBerardinis RJ . Metabolic pathways promoting cancer cell survival and growth. Nat Cell Biol 2015; 17: 351–359.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Kroemer G, Pouyssegur J . Tumor cell metabolism: cancer's Achilles' heel. Cancer Cell 2008; 13: 472–482.

    CAS  PubMed  Google Scholar 

  8. Ward PS, Thompson CB . Metabolic reprogramming: a cancer hallmark even warburg did not anticipate. Cancer Cell 2012; 21: 297–308.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Yuneva MO, Fan TW, Allen TD, Higashi RM, Ferraris DV, Tsukamoto T et al. The metabolic profile of tumors depends on both the responsible genetic lesion and tissue type. Cell Metab 2012; 15: 157–170.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. DeBerardinis RJ, Mancuso A, Daikhin E, Nissim I, Yudkoff M, Wehrli S et al. Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc Natl Acad Sci USA 2007; 104: 19345–19350.

    CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  12. Flier JS, Mueckler MM, Usher P, Lodish HF . Elevated levels of glucose transport and transporter messenger RNA are induced by ras or src oncogenes. Science 1987; 235: 1492–1495.

    CAS  PubMed  Google Scholar 

  13. Warburg O . On respiratory impairment in cancer cells. Science 1956; 124: 269–270.

    CAS  PubMed  Google Scholar 

  14. Abildgaard C, Guldberg P . Molecular drivers of cellular metabolic reprogramming in melanoma. Trends Mol Med 2015; 21: 164–171.

    CAS  PubMed  Google Scholar 

  15. Garraway LA, Widlund HR, Rubin MA, Getz G, Berger AJ, Ramaswamy S et al. Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma. Nature 2005; 436: 117–122.

    CAS  PubMed  Google Scholar 

  16. Yokoyama S, Woods SL, Boyle GM, Aoude LG, MacGregor S, Zismann V et al. A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma. Nature 2011; 480: 99–103.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Muller J, Krijgsman O, Tsoi J, Robert L, Hugo W, Song C et al. Low MITF/AXL ratio predicts early resistance to multiple targeted drugs in melanoma. Nat Commun 2014; 5: 5712.

    PubMed  Google Scholar 

  18. Kraehn GM, Utikal J, Udart M, Greulich KM, Bezold G, Kaskel P et al. Extra c-myc oncogene copies in high risk cutaneous malignant melanoma and melanoma metastases. Br J Cancer 2001; 84: 72–79.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Moore SR, Persons DL, Sosman JA, Bobadilla D, Bedell V, Smith DD et al. Detection of copy number alterations in metastatic melanoma by a DNA fluorescence in situ hybridization probe panel and array comparative genomic hybridization: a southwest oncology group study (S9431). Clin Cancer Res 2008; 14: 2927–2935.

    CAS  PubMed  Google Scholar 

  20. Falck Miniotis M, Arunan V, Eykyn TR, Marais R, Workman P, Leach MO et al. MEK1/2 inhibition decreases lactate in BRAF-driven human cancer cells. Cancer Res 2013; 73: 4039–4049.

    CAS  PubMed  Google Scholar 

  21. Olenchock BA, Vander Heiden MG . Pyruvate as a pivot point for oncogene-induced senescence. Cell 2013; 153: 1429–1430.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Haq R, Shoag J, Andreu-Perez P, Yokoyama S, Edelman H, Rowe GC et al. Oncogenic BRAF regulates oxidative metabolism via PGC1alpha and MITF. Cancer Cell 2013; 23: 302–315.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Deberardinis RJ, Sayed N, Ditsworth D, Thompson CB . Brick by brick: metabolism and tumor cell growth. Curr Opin Genet Dev 2008; 18: 54–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Lunt SY, Vander Heiden MG . Aerobic glycolysis: meeting the metabolic requirements of cell proliferation. Annu Rev Cell Dev Biol 2011; 27: 441–464.

    CAS  PubMed  Google Scholar 

  25. Scott DA, Richardson AD, Filipp FV, Knutzen CA, Chiang GG, Ronai ZA et al. Comparative metabolic flux profiling of melanoma cell lines: beyond the Warburg effect. J Biol Chem 2011; 286: 42626–42634.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Majmundar AJ, Wong WJ, Simon MC . Hypoxia-inducible factors and the response to hypoxic stress. Mol Cell 2010; 40: 294–309.

    CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  Google Scholar 

  28. Papandreou I, Cairns RA, Fontana L, Lim AL, Denko NC . HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab 2006; 3: 187–197.

    CAS  PubMed  Google Scholar 

  29. Mazure NM, Chen EY, Yeh P, Laderoute KR, Giaccia AJ . Oncogenic transformation and hypoxia synergistically act to modulate vascular endothelial growth factor expression. Cancer Res 1996; 56: 3436–3440.

    CAS  PubMed  Google Scholar 

  30. Jiang BH, Agani F, Passaniti A, Semenza GL . 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 1997; 57: 5328–5335.

    CAS  PubMed  Google Scholar 

  31. Sheta EA, Trout H, Gildea JJ, Harding MA, Theodorescu D . Cell density mediated pericellular hypoxia leads to induction of HIF-1alpha via nitric oxide and Ras/MAP kinase mediated signaling pathways. Oncogene 2001; 20: 7624–7634.

    CAS  PubMed  Google Scholar 

  32. Kuphal S, Winklmeier A, Warnecke C, Bosserhoff AK . Constitutive HIF-1 activity in malignant melanoma. Eur J Cancer 2010; 46: 1159–1169.

    CAS  PubMed  Google Scholar 

  33. Koch A, Lang SA, Wild PJ, Gantner S, Mahli A, Spanier G et al. Glucose transporter isoform 1 expression enhances metastasis of malignant melanoma cells. Oncotarget 2015; 6: 32748–32760.

    PubMed  PubMed Central  Google Scholar 

  34. Ho J, de Moura MB, Lin Y, Vincent G, Thorne S, Duncan LM et al. Importance of glycolysis and oxidative phosphorylation in advanced melanoma. Mol Cancer 2012; 11: 76.

    CAS  PubMed  PubMed Central  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  36. Firth JD, Ebert BL, Ratcliffe PJ . Hypoxic regulation of lactate dehydrogenase A. Interaction between hypoxia-inducible factor 1 and cAMP response elements. J Biol Chem 1995; 270: 21021–21027.

    CAS  PubMed  Google Scholar 

  37. Wise DR, Thompson CB . Glutamine addiction: a new therapeutic target in cancer. Trends Biochem Sci 2010; 35: 427–433.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Filipp FV, Scott DA, Ronai ZA, Osterman AL, Smith JW . Reverse TCA cycle flux through isocitrate dehydrogenases 1 and 2 is required for lipogenesis in hypoxic melanoma cells. Pigment Cell Melanoma Res 2012; 25: 375–383.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Metallo CM, Gameiro PA, Bell EL, Mattaini KR, Yang J, Hiller K et al. Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature 2012; 481: 380–384.

    CAS  Google Scholar 

  40. Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim SH et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases. Cancer Cell 2011; 19: 17–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Zhao S, Lin Y, Xu W, Jiang W, Zha Z, Wang P et al. Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1alpha. Science 2009; 324: 261–265.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Chowdhury R, Yeoh KK, Tian YM, Hillringhaus L, Bagg EA, Rose NR et al. The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases. EMBO Rep 2011; 12: 463–469.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Lian CG, Xu Y, Ceol C, Wu F, Larson A, Dresser K et al. Loss of 5-hydroxymethylcytosine is an epigenetic hallmark of melanoma. Cell 2012; 150: 1135–1146.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Shibata T, Kokubu A, Miyamoto M, Sasajima Y, Yamazaki N . Mutant IDH1 confers an in vivo growth in a melanoma cell line with BRAF mutation. Am J Pathol 2011; 178: 1395–1402.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Amelio I, Cutruzzola F, Antonov A, Agostini M, Melino G . Serine and glycine metabolism in cancer. Trends Biochem Sci 2014; 39: 191–198.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Labuschagne CF, van den Broek NJ, Mackay GM, Vousden KH, Maddocks OD . Serine, but not glycine, supports one-carbon metabolism and proliferation of cancer cells. Cell Rep 2014; 7: 1248–1258.

    CAS  PubMed  Google Scholar 

  47. Locasale JW . Serine, glycine and one-carbon units: cancer metabolism in full circle. Nat Rev Cancer 2013; 13: 572–583.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Ye J, Fan J, Venneti S, Wan YW, Pawel BR, Zhang J et al. Serine catabolism regulates mitochondrial redox control during hypoxia. Cancer Discov 2014; 4: 1406–1417.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Beroukhim R, Mermel CH, Porter D, Wei G, Raychaudhuri S, Donovan J et al. The landscape of somatic copy-number alteration across human cancers. Nature 2010; 463: 899–905.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Mullarky E, Mattaini KR, Vander Heiden MG, Cantley LC, Locasale JW . PHGDH amplification and altered glucose metabolism in human melanoma. Pigment Cell Melanoma Res 2011; 24: 1112–1115.

    CAS  PubMed  Google Scholar 

  51. Locasale JW, Grassian AR, Melman T, Lyssiotis CA, Mattaini KR, Bass AJ et al. Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis. Nat Genet 2011; 43: 869–874.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Possemato R, Marks KM, Shaul YD, Pacold ME, Kim D, Birsoy K et al. Functional genomics reveal that the serine synthesis pathway is essential in breast cancer. Nature 2011; 476: 346–350.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Ratnikov B, Aza-Blanc P, Ronai ZA, Smith JW, Osterman AL, Scott DA . Glutamate and asparagine cataplerosis underlie glutamine addiction in melanoma. Oncotarget 2015; 6: 7379–7389.

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  55. Ye J, Mancuso A, Tong X, Ward PS, Fan J, Rabinowitz JD et al. Pyruvate kinase M2 promotes de novo serine synthesis to sustain mTORC1 activity and cell proliferation. Proc Natl Acad Sci USA 2012; 109: 6904–6909.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Israelsen WJ, Dayton TL, Davidson SM, Fiske BP, Hosios AM, Bellinger G et al. PKM2 isoform-specific deletion reveals a differential requirement for pyruvate kinase in tumor cells. Cell 2013; 155: 397–409.

    CAS  PubMed  Google Scholar 

  57. Lunt SY, Muralidhar V, Hosios AM, Israelsen WJ, Gui DY, Newhouse L et al. Pyruvate kinase isoform expression alters nucleotide synthesis to impact cell proliferation. Mol Cell 2015; 57: 95–107.

    CAS  PubMed  Google Scholar 

  58. Gupta V, Wellen KE, Mazurek S, Bamezai RN . Pyruvate kinase M2: regulatory circuits and potential for therapeutic intervention. Curr Pharm Des 2014; 20: 2595–2606.

    CAS  PubMed  Google Scholar 

  59. Li Y, Luo S, Ma R, Liu J, Xu P, Zhang H et al. Upregulation of cytosolic phosphoenolpyruvate carboxykinase is a critical metabolic event in melanoma cells that repopulate tumors. Cancer Res 2015; 75: 1191–1196.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Wawrzyniak JA, Bianchi-Smiraglia A, Bshara W, Mannava S, Ackroyd J, Bagati A et al. A purine nucleotide biosynthesis enzyme guanosine monophosphate reductase is a suppressor of melanoma invasion. Cell Rep 2013; 5: 493–507.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Kaplon J, Zheng L, Meissl K, Chaneton B, Selivanov VA, Mackay G et al. A key role for mitochondrial gatekeeper pyruvate dehydrogenase in oncogene-induced senescence. Nature 2013; 498: 109–112.

    CAS  PubMed  Google Scholar 

  62. Michaloglou C, Vredeveld LC, Soengas MS, Denoyelle C, Kuilman T, van der Horst CM et al. BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 2005; 436: 720–724.

    CAS  PubMed  Google Scholar 

  63. Patel MS, Korotchkina LG . Regulation of the pyruvate dehydrogenase complex. Biochem Soc Trans 2006; 34: 217–222.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Schell JC, Olson KA, Jiang L, Hawkins AJ, Van Vranken JG, Xie J et al. A role for the mitochondrial pyruvate carrier as a repressor of the Warburg effect and colon cancer cell growth. Mol Cell 2014; 56: 400–413.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Vacanti NM, Divakaruni AS, Green CR, Parker SJ, Henry RR, Ciaraldi TP et al. Regulation of substrate utilization by the mitochondrial pyruvate carrier. Mol Cell 2014; 56: 425–435.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Yang C, Ko B, Hensley CT, Jiang L, Wasti AT, Kim J et al. Glutamine oxidation maintains the TCA cycle and cell survival during impaired mitochondrial pyruvate transport. Mol Cell 2014; 56: 414–424.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Filipp FV, Ratnikov B, De Ingeniis J, Smith JW, Osterman AL, Scott DA . Glutamine-fueled mitochondrial metabolism is decoupled from glycolysis in melanoma. Pigment Cell Melanoma Res 2012; 25: 732–739.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Yuneva M, Zamboni N, Oefner P, Sachidanandam R, Lazebnik Y . Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells. J Cell Biol 2007; 178: 93–105.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Zhang J, Fan J, Venneti S, Cross JR, Takagi T, Bhinder B et al. Asparagine plays a critical role in regulating cellular adaptation to glutamine depletion. Mol Cell 2014; 56: 205–218.

    CAS  PubMed  PubMed Central  Google Scholar 

  71. DeBerardinis RJ, Cheng T . Q's next: the diverse functions of glutamine in metabolism, cell biology and cancer. Oncogene 2010; 29: 313–324.

    CAS  PubMed  Google Scholar 

  72. Cassago A, Ferreira AP, Ferreira IM, Fornezari C, Gomes ER, Greene KS et al. Mitochondrial localization and structure-based phosphate activation mechanism of Glutaminase C with implications for cancer metabolism. Proc Natl Acad Sci USA 2012; 109: 1092–1097.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. van den Heuvel AP, Jing J, Wooster RF, Bachman KE . Analysis of glutamine dependency in non-small cell lung cancer: GLS1 splice variant GAC is essential for cancer cell growth. Cancer Biol Ther 2012; 13: 1185–1194.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Birsoy K, Wang T, Chen WW, Freinkman E, Abu-Remaileh M, Sabatini DM . An essential role of the mitochondrial electron transport chain in cell proliferation is to enable aspartate synthesis. Cell 2015; 162: 540–551.

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Sullivan LB, Gui DY, Hosios AM, Bush LN, Freinkman E, Vander Heiden MG . Supporting aspartate biosynthesis is an essential function of respiration in proliferating cells. Cell 2015; 162: 552–563.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Harris M . Pyruvate blocks expression of sensitivity to antimycin A and chloramphenicol. Somatic Cell Genet 1980; 6: 699–708.

    CAS  PubMed  Google Scholar 

  77. Van Vranken JG, Rutter J . You down with ETC? Yeah, you know D!. Cell 2015; 162: 471–473.

    CAS  PubMed  Google Scholar 

  78. De Ingeniis J, Ratnikov B, Richardson AD, Scott DA, Aza-Blanc P, De SK et al. Functional specialization in proline biosynthesis of melanoma. PLoS One 2012; 7: e45190.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Dang CV . MYC on the path to cancer. Cell 2012; 149: 22–35.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Liu W, Le A, Hancock C, Lane AN, Dang CV, Fan TW et al. Reprogramming of proline and glutamine metabolism contributes to the proliferative and metabolic responses regulated by oncogenic transcription factor c-MYC. Proc Natl Acad Sci USA 2012; 109: 8983–8988.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Wishart DS, Jewison T, Guo AC, Wilson M, Knox C, Liu Y et al. HMDB 3.0—the human metabolome database in 2013. Nucleic Acids Res 2013; 41: D801–D807.

    CAS  PubMed  Google Scholar 

  82. Kang HB, Fan J, Lin R, Elf S, Ji Q, Zhao L et al. Metabolic rewiring by oncogenic BRAF V600E links ketogenesis pathway to BRAF-MEK1 signaling. Mol Cell 2015; 59: 345–358.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. McPherson PA, McEneny J . The biochemistry of ketogenesis and its role in weight management, neurological disease and oxidative stress. J Physiol Biochem 2012; 68: 141–151.

    CAS  PubMed  Google Scholar 

  84. Puigserver P, Spiegelman BM . Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha): transcriptional coactivator and metabolic regulator. Endocr Rev 2003; 24: 78–90.

    CAS  PubMed  Google Scholar 

  85. Haq R, Fisher DE . Biology and clinical relevance of the micropthalmia family of transcription factors in human cancer. J Clin Oncol 2011; 29: 3474–3482.

    CAS  PubMed  Google Scholar 

  86. Bertolotto C, Lesueur F, Giuliano S, Strub T, de Lichy M, Bille K et al. A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma. Nature 2011; 480: 94–98.

    CAS  PubMed  Google Scholar 

  87. Vazquez F, Lim JH, Chim H, Bhalla K, Girnun G, Pierce K et al. PGC1alpha expression defines a subset of human melanoma tumors with increased mitochondrial capacity and resistance to oxidative stress. Cancer Cell 2013; 23: 287–301.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Mootha VK, Lindgren CM, Eriksson KF, Subramanian A, Sihag S, Lehar J et al. PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet 2003; 34: 267–273.

    CAS  PubMed  Google Scholar 

  89. Bogunovic D, O'Neill DW, Belitskaya-Levy I, Vacic V, Yu YL, Adams S et al. Immune profile and mitotic index of metastatic melanoma lesions enhance clinical staging in predicting patient survival. Proc Natl Acad Sci USA 2009; 106: 20429–20434.

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Niehr F, von Euw E, Attar N, Guo D, Matsunaga D, Sazegar H et al. Combination therapy with vemurafenib (PLX4032/RG7204) and metformin in melanoma cell lines with distinct driver mutations. J Transl Med 2011; 9: 76.

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Yuan P, Ito K, Perez-Lorenzo R, Del Guzzo C, Lee JH, Shen CH et al. Phenformin enhances the therapeutic benefit of BRAF(V600E) inhibition in melanoma. Proc Natl Acad Sci USA 2013; 110: 18226–18231.

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Roesch A, Fukunaga-Kalabis M, Schmidt EC, Zabierowski SE, Brafford PA, Vultur A et al. A temporarily distinct subpopulation of slow-cycling melanoma cells is required for continuous tumor growth. Cell 2010; 141: 583–594.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Janzer A, German NJ, Gonzalez-Herrera KN, Asara JM, Haigis MC, Struhl K . Metformin and phenformin deplete tricarboxylic acid cycle and glycolytic intermediates during cell transformation and NTPs in cancer stem cells. Proc Natl Acad Sci USA 2014; 111: 10574–10579.

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Baenke F, Chaneton B, Smith M, Van Den Broek N, Hogan K, Tang H et al. Resistance to BRAF inhibitors induces glutamine dependency in melanoma cells. Mol Oncol 2015; 10: 73–84.

    PubMed  PubMed Central  Google Scholar 

  95. Hernandez-Davies JE, Tran TQ, Reid MA, Rosales KR, Lowman XH, Pan M et al. Vemurafenib resistance reprograms melanoma cells towards glutamine dependence. J Transl Med 2015; 13: 210.

    PubMed  PubMed Central  Google Scholar 

  96. Bamford S, Dawson E, Forbes S, Clements J, Pettett R, Dogan A et al. The COSMIC (Catalogue of Somatic Mutations in Cancer) database and website. Br J Cancer 2004; 91: 355–358.

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Schubbert S, Shannon K, Bollag G . Hyperactive Ras in developmental disorders and cancer. Nat Rev Cancer 2007; 7: 295–308.

    CAS  PubMed  Google Scholar 

  98. Gaglio D, Metallo CM, Gameiro PA, Hiller K, Danna LS, Balestrieri C et al. Oncogenic K-Ras decouples glucose and glutamine metabolism to support cancer cell growth. Mol Syst Biol 2011; 7: 523.

    PubMed  PubMed Central  Google Scholar 

  99. Son J, Lyssiotis CA, Ying H, Wang X, Hua S, Ligorio M et al. Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature 2013; 496: 101–105.

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Ying H, Kimmelman AC, Lyssiotis CA, Hua S, Chu GC, Fletcher-Sananikone E et al. Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell 2012; 149: 656–670.

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Yun J, Mullarky E, Lu C, Bosch KN, Kavalier A, Rivera K et al. Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH. Science 2015; 350: 1391–1396.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Weinberg F, Hamanaka R, Wheaton WW, Weinberg S, Joseph J, Lopez M et al. Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity. Proc Natl Acad Sci USA 2010; 107: 8788–8793.

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Hanahan D, Weinberg RA . Hallmarks of cancer: the next generation. Cell 2011; 144: 646–674.

    CAS  PubMed  Google Scholar 

  104. Weinberg F, Chandel NS . Mitochondrial metabolism and cancer. Ann NY Acad Sci 2009; 1177: 66–73.

    CAS  PubMed  Google Scholar 

  105. Diehn M, Cho RW, Lobo NA, Kalisky T, Dorie MJ, Kulp AN et al. Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature 2009; 458: 780–783.

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Trachootham D, Alexandre J, Huang P . Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach? Nat Rev Drug Discov 2009; 8: 579–591.

    CAS  PubMed  Google Scholar 

  107. Schieber M, Chandel NS . ROS function in redox signaling and oxidative stress. Curr Biol 2014; 24: R453–R462.

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Gorrini C, Harris IS, Mak TW . Modulation of oxidative stress as an anticancer strategy. Nat Rev Drug Discov 2013; 12: 931–947.

    CAS  PubMed  Google Scholar 

  109. Padmanabhan B, Tong KI, Ohta T, Nakamura Y, Scharlock M, Ohtsuji M et al. Structural basis for defects of Keap1 activity provoked by its point mutations in lung cancer. Mol Cell 2006; 21: 689–700.

    CAS  PubMed  Google Scholar 

  110. Singh A, Misra V, Thimmulappa RK, Lee H, Ames S, Hoque MO et al. Dysfunctional KEAP1-NRF2 interaction in non-small-cell lung cancer. PLoS Med 2006; 3: e420.

    PubMed  PubMed Central  Google Scholar 

  111. St-Pierre J, Drori S, Uldry M, Silvaggi JM, Rhee J, Jager S et al. Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell 2006; 127: 397–408.

    CAS  PubMed  Google Scholar 

  112. Handschin C, Chin S, Li P, Liu F, Maratos-Flier E, Lebrasseur NK et al. Skeletal muscle fiber-type switching, exercise intolerance, and myopathy in PGC-1alpha muscle-specific knock-out animals. J Biol Chem 2007; 282: 30014–30021.

    CAS  PubMed  Google Scholar 

  113. Godic A, Poljsak B, Adamic M, Dahmane R . The role of antioxidants in skin cancer prevention and treatment. Oxid Med Cell Longev 2014; 2014: 860479.

    PubMed  PubMed Central  Google Scholar 

  114. Westerlund A, Steineck G, Balter K, Stattin P, Gronberg H, Hedelin M . Dietary supplement use patterns in men with prostate cancer: the Cancer Prostate Sweden study. Ann Oncol 2011; 22: 967–972.

    CAS  PubMed  Google Scholar 

  115. Willcox JK, Ash SL, Catignani GL . Antioxidants and prevention of chronic disease. Crit Rev Food Sci Nutr 2004; 44: 275–295.

    CAS  PubMed  Google Scholar 

  116. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. N Engl J Med 1994; 330: 1029–1035.

    Google Scholar 

  117. Goodman M, Bostick RM, Kucuk O, Jones DP . Clinical trials of antioxidants as cancer prevention agents: past, present, and future. Free Radic Biol Med 2011; 51: 1068–1084.

    CAS  PubMed  Google Scholar 

  118. Leo MA, Lieber CS . Re: Risk factors for lung cancer and for intervention effects in CARET, the Beta-Carotene and Retinol Efficacy Trial. J Natl Cancer Inst 1997; 89: 1722–1723.

    CAS  PubMed  Google Scholar 

  119. DeNicola GM, Karreth FA, Humpton TJ, Gopinathan A, Wei C, Frese K et al. Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature 2011; 475: 106–109.

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Dey S, Sayers CM, Verginadis II, Lehman SL, Cheng Y, Cerniglia GJ et al. ATF4-dependent induction of heme oxygenase 1 prevents anoikis and promotes metastasis. J Clin Invest 2015; 125: 2592–2608.

    PubMed  PubMed Central  Google Scholar 

  121. Harris IS, Treloar AE, Inoue S, Sasaki M, Gorrini C, Lee KC et al. Glutathione and thioredoxin antioxidant pathways synergize to drive cancer initiation and progression. Cancer Cell 2015; 27: 211–222.

    CAS  PubMed  Google Scholar 

  122. Sayin VI, Ibrahim MX, Larsson E, Nilsson JA, Lindahl P, Bergo MO . Antioxidants accelerate lung cancer progression in mice. Sci Transl Med 2014; 6: 221ra215.

    PubMed  Google Scholar 

  123. Le Gal K, Ibrahim MX, Wiel C, Sayin VI, Akula MK, Karlsson C et al. Antioxidants can increase melanoma metastasis in mice. Sci Transl Med 2015; 7: 308re308.

    Google Scholar 

  124. Piskounova E, Agathocleous M, Murphy MM, Hu Z, Huddlestun SE, Zhao Z et al. Oxidative stress inhibits distant metastasis by human melanoma cells. Nature 2015; 527: 186–191.

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Dankort D, Curley DP, Cartlidge RA, Nelson B, Karnezis AN, Damsky WE Jr et al. Braf(V600E) cooperates with Pten loss to induce metastatic melanoma. Nat Genet 2009; 41: 544–552.

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Hobbs GA, Zhou B, Cox AD, Campbell SL . Rho GTPases, oxidation, and cell redox control. Small GTPases 2014; 5: e28579.

    PubMed  PubMed Central  Google Scholar 

  127. Hobbs GA, Mitchell LE, Arrington ME, Gunawardena HP, DeCristo MJ, Loeser RF et al. Redox regulation of Rac1 by thiol oxidation. Free Radic Biol Med 2015; 79: 237–250.

    CAS  PubMed  Google Scholar 

  128. Mitchell L, Hobbs GA, Aghajanian A, Campbell SL . Redox regulation of Ras and Rho GTPases: mechanism and function. Antioxid Redox Signal 2013; 18: 250–258.

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Fan J, Ye J, Kamphorst JJ, Shlomi T, Thompson CB, Rabinowitz JD . Quantitative flux analysis reveals folate-dependent NADPH production. Nature 2014; 510: 298–302.

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Lewis CA, Parker SJ, Fiske BP, McCloskey D, Gui DY, Green CR et al. Tracing compartmentalized NADPH metabolism in the cytosol and mitochondria of mammalian cells. Mol Cell 2014; 55: 253–263.

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Mari M, Morales A, Colell A, Garcia-Ruiz C, Fernandez-Checa JC . Mitochondrial glutathione, a key survival antioxidant. Antioxid Redox Signal 2009; 11: 2685–2700.

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Dupuy F, Tabaries S, Andrzejewski S, Dong Z, Blagih J, Annis MG et al. PDK1-dependent metabolic reprogramming dictates metastatic potential in breast cancer. Cell Metab 2015; 22: 577–589.

    CAS  PubMed  Google Scholar 

  133. Kaufman HL, Kirkwood JM, Hodi FS, Agarwala S, Amatruda T, Bines SD et al. The Society for Immunotherapy of Cancer consensus statement on tumour immunotherapy for the treatment of cutaneous melanoma. Nat Rev Clin Oncol 2013; 10: 588–598.

    CAS  PubMed  Google Scholar 

  134. Shtivelman E, Davies MQ, Hwu P, Yang J, Lotem M, Oren M et al. Pathways and therapeutic targets in melanoma. Oncotarget 2014; 5: 1701–1752.

    PubMed  PubMed Central  Google Scholar 

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  1. Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA

    B I Ratnikov, D A Scott, A L Osterman, J W Smith & Z A Ronai

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Ratnikov, B., Scott, D., Osterman, A. et al. Metabolic rewiring in melanoma. Oncogene 36, 147–157 (2017). https://doi.org/10.1038/onc.2016.198

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