Fundamentals of cancer metabolism

Science Advances

Volumn 2, Issue 5, 2016, Pages

  De Berardinis, Ralph J ^a   Chandel, Navdeep S ^b  

^a UNIVERSITY OF TEXAS AT DALLAS   (United States)

^b NORTHWESTERN UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

DISEASES; PHYSIOLOGY; TUMORS;

CONCEPTUAL FRAMEWORKS; HUMAN CANCER; MALIGNANT CELLS; NUTRIENT ACQUISITION; TUMOR CELLS; TUMORIGENESIS;

METABOLISM;

MACROMOLECULE; REACTIVE OXYGEN METABOLITE;

ANIMAL; ENERGY METABOLISM; HUMAN; MACROMOLECULE; METABOLISM; MITOCHONDRION; MOLECULARLY TARGETED THERAPY; NEOPLASMS; OXIDATION REDUCTION REACTION; SIGNAL TRANSDUCTION;

ANIMALS; ENERGY METABOLISM; HUMANS; MACROMOLECULAR SUBSTANCES; METABOLIC NETWORKS AND PATHWAYS; MITOCHONDRIA; MOLECULAR TARGETED THERAPY; NEOPLASMS; OXIDATION-REDUCTION; REACTIVE OXYGEN SPECIES; SIGNAL TRANSDUCTION;

EID: 84990224053     PISSN: None     EISSN: 23752548     Source Type: Journal    
DOI: 10.1126/sciadv.1600200     Document Type: Review

References (200)

1. D. Hanahan, R. A. Weinberg, Hallmarks of cancer: The next generation. Cell 144, 646-674 (2011
2. N. N. Pavlova, C. B. Thompson, The emerging hallmarks of cancer metabolism. Cell Metab. 23, 27-47 (2016
3. K. C. Patra, Q. Wang, P. T. Bhaskar, L. Miller, Z. Wang, W. Wheaton, N. Chandel, M. Laakso, W. J. Muller, E. L. Allen, A. K. Jha, G. A. Smolen, M. F. Clasquin, R. B. Robey, N. Hay, Hexokinase 2 is required for tumor initiation and maintenance and its systemic deletion is therapeutic in mouse models of cancer. Cancer Cell 24, 213-228 (2013
4. E. H. Shroff, L. S. Eberlin, V. M. Dang, A. M. Gouw, M. Gabay, S. J. Adam, D. I. Bellovin, P. T. Tran, W. M. Philbrick, A. Garcia-Ocana, S. C. Casey, Y. Li, C. V. Dang, R. N. Zare, D. W. Felshera, MYC oncogene overexpression drives renal cell carcinoma in a mouse model through glutamine metabolism. Proc. Natl. Acad. Sci. U.S.A. 112, 6539-6544 (2015
5. L. A. Clavell, R. D. Gelber, H. J. Cohen, S. Hitchcock-Bryan, J. R. Cassady, N. J. Tarbell, S. R. Blattner, R. Tantravahi, P. Leavitt, S. E. Sallan, Four-Agent induction and intensive asparaginase therapy for treatment of childhood acute lymphoblastic leukemia. N. Engl. J. Med. 315, 657-663 (1986
6. J. Yun, C. Rago, I. Cheong, R. Pagliarini, P. Angenendt, H. Rajagopalan, K. Schmidt, J. K. Willson, S. Markowitz, S. Zhou, L. A. Diaz Jr., V. E. Velculescu, C. Lengauer, K. W. Kinzler, B. Vogelstein, N. Papadopoulos, Glucose deprivation contributes to the development of KRAS pathway mutations in tumor cells. Science 325, 1555-1559 (2009
7. J. M. Loo, A. Scherl, A. Nguyen, F. Y. Man, E. Weinberg, Z. Zeng, L. Saltz, P. B. Paty, S. F. Tavazoie, Extracellular metabolic energetics can promote cancer progression. Cell 160, 393-406 (2015
8. E. Piskounova, M. Agathocleous, M. M. Murphy, Z. Hu, S. E. Huddlestun, Z. Zhao, A. M. Leitch, T. M. Johnson, R. J. DeBerardinis, S. J. Morrison, Oxidative stress inhibits distant metastasis by human melanoma cells. Nature 527, 186-191 (2015
9. L. K. Boroughs, R. J. DeBerardinis, Metabolic pathways promoting cancer cell survival and growth. Nat. Cell Biol. 17, 351-359 (2015
10. P. S. Ward, C. B. Thompson, Metabolic reprogramming: A cancer hallmark even Warburg did not anticipate. Cancer Cell 21, 297-308 (2012
11. S. Y. Lunt, M. G. Vander Heiden, Aerobic glycolysis: Meeting the metabolic requirements of cell proliferation. Annu. Rev. Cell Dev. Biol. 27, 441-464 (2011
12. W. H. Koppenol, P. L. Bounds, C. V. Dang, Otto Warburg's contributions to current concepts of cancer metabolism. Nat. Rev. Cancer 11, 325-337 (2011
13. C. S. Ahn, C. M. Metallo, Mitochondria as biosynthetic factories for cancer proliferation. Cancer Metab. 3, 1 (2015
14. O. E. Owen, S. C. Kalhan, R. W. Hanson, The key role of anaplerosis and cataplerosis for citric acid cycle function. J. Biol. Chem. 277, 30409-30412 (2002
15. J. R. Cantor, D. M. Sabatini, Cancer cell metabolism: One hallmark, many faces. Cancer Discov. 2, 881-898 (2012
16. C. C. Dibble, B. D. Manning, Signal integration by mTORC1 coordinates nutrient input with biosynthetic output. Nat. Cell Biol. 15, 555-564 (2013
17. T. L. Yuan, L. C. Cantley, PI3K pathway alterations in cancer: Variations on a theme. Oncogene 27, 5497-5510 (2008
18. Z. E. Stine, Z. E. Walton, B. J. Altman, A. L. Hsieh, C. V. Dang, MYC, metabolism, and cancer. Cancer Discov. 5, 1024-1039 (2015
19. F. Kruiswijk, C. F. Labuschagne, K. H. Vousden, p53 in survival, death and metabolic health: A lifeguard with a licence to kill. Nat. Rev. Mol. Cell Biol. 16, 393-405 (2015
20. L. Jiang, N. Kon, T. Li, S. J. Wang, T. Su, H. Hibshoosh, R. Baer, W. Gu, Ferroptosis as a p53-mediated activity during tumour suppression. Nature 520, 57-62 (2015
21. T. Li, N. Kon, L. Jiang, M. Tan, T. Ludwig, Y. Zhao, R. Baer, W. Gu, Tumor suppression in the absence of p53-mediated cell-cycle arrest, apoptosis, and senescence. Cell 149, 1269-1283 (2012
22. R. K. Jain, L. L. Munn, D. Fukumura, Dissecting tumour pathophysiology using intravital microscopy. Nat. Rev. Cancer 2, 266-276 (2002
23. G.L. Semenza, Hypoxia-inducible factors in physiology and medicine. Cell 148, 399-408 (2012
24. W. G. Kaelin Jr., P. J. Ratcliffe, Oxygen sensing by metazoans: The central role of the HIF hydroxylase pathway. Mol. Cell 30, 393-402 (2008
25. R. Possemato, K. M. Marks, Y. D. Shaul, M. E. Pacold, D. Kim, K. Birsoy, S. Sethumadhavan, H.-K. Woo, H. G. Jang, A. K. Jha, W. W. Chen, F. G. Barrett, N. Stransky, Z.-Y. Tsun, G. S. Cowley, J. Barretina, N. Y. Kalaany, P. P. Hsu, K. Ottina, A. M. Chan, B. Yuan, L. A. Garraway, D. E. Root, M. Mino-Kenudson, E. F. Brachtel, E. M. Driggers, D. M. Sabatini, Functional genomics reveal that the serine synthesis pathway is essential in breast cancer. Nature 476, 346-350 (2011
26. J. W. Locasale, A. R. Grassian, T. Melman, C. A. Lyssiotis, K. R. Mattaini, A. J. Bass, G. Heffron, C. M. Metallo, T. Muranen, H. Sharfi, A. T. Sasaki, D. Anastasiou, E. Mullarky, N. I. Vokes, M. Sasaki, R. Beroukhim, G. Stephanopoulos, A. H. Ligon, M. Meyerson, A. L. Richardson, L. Chin, G. Wagner, J. M. Asara, J. S. Brugge, L. C. Cantley, M. G. Vander Heiden, Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis. Nat. Genet. 43, 869-874 (2011
27. J. W. Locasale, Serine, glycine and one-carbon units: Cancer metabolism in full circle. Nat. Rev. Cancer 13, 572-583 (2013
28. M. Yang, T. Soga, P. J. Pollard, Oncometabolites: Linking altered metabolism with cancer. J. Clin. Invest. 123, 3652-3658 (2013
29. H. Yan, D. W. Parsons, G. Jin, R. McLendon, B. A. Rasheed, W. Yuan, I. Kos, I. Batinic-Haberle, S. Jones, G. J. Riggins, H. Friedman, A. Friedman, D. Reardon, J. Herndon, K. W. Kinzler, V. E. Velculescu, B. Vogelstein, D. D. Bigner, IDH1 and IDH2 mutations in gliomas. N. Engl. J. Med. 360, 765-773 (2009
30. E. R. Mardis, L. Ding, D. J. Dooling, D. E. Larson, M. D. McLellan, K. Chen, D. C. Koboldt, R. S. Fulton, K. D. Delehaunty, S. D. McGrath, L. A. Fulton, D. P. Locke, V. J. Magrini, R. M. Abbott, T. L. Vickery, J. S. Reed, J. S. Robinson, T. Wylie, S. M. Smith, L. Carmichael, J. M. Eldred, C. C. Harris, J. Walker, J. B. Peck, F. Du, A. F. Dukes, G. E. Sanderson, A. M. Brummett, E. Clark, J. F. McMichael, R. J. Meyer, J. K. Schindler, C. S. Pohl, J. W. Wallis, X. Shi, L. Lin, H. Schmidt, Y. Tang, C. Haipek, M. E. Wiechert, J. V. Ivy, J. Kalicki, G. Elliott, R. E. Ries, J. E. Payton, P. Westervelt, M. H. Tomasson, M. A. Watson, J. Baty, S. Heath, W. D. Shannon, R. Nagarajan, D. C. Link, M. J. Walter, T. A. Graubert, J. F. DiPersio, R. K. Wilson, T. J. Ley, Recurring mutations found by sequencing an acute myeloid leukemia genome. N. Engl. J. Med. 361, 1058-1066 (2009
31. M. R. Kang, M. S. Kim, J. E. Oh, Y. R. Kim, S. Y. Song, S. I. Seo, J. Y. Lee, N. J. Yoo, S. H. Lee, Mutational analysis of IDH1 codon 132 in glioblastomas and other common cancers. Int. J. Cancer 125, 353-355 (2009
32. J.-A. Losman, W. G. Kaelin Jr., What a difference a hydroxyl makes: Mutant IDH, (R)-2-hydroxyglutarate, and cancer. Genes Dev. 27, 836-852 (2013
33. L. Dang, D. W. White, S. Gross, B. D. Bennett, M. A. Bittinger, E. M. Driggers, V. R. Fantin, H. G. Jang, S. Jin, M. C. Keenan, K. M. Marks, R. M. Prins, P. S. Ward, K. E. Yen, L. M. Liau, J. D. Rabinowitz, L. C. Cantley, C. B. Thompson, M. G. Vander Heiden, S. M. Su, Cancerassociated IDH1 mutations produce 2-hydroxyglutarate. Nature 465, 966 (2010
34. P. S. Ward, J. Patel, D. R. Wise, O. Abdel-Wahab, B. D. Bennett, H. A. Coller, J. R. Cross, V. R. Fantin, C. V. Hedvat, A. E. Perl, J. D. Rabinowitz, M. Carroll, S. M. Su, K. A. Sharp, R. L. Levine, C. B. Thompson, The common feature of leukemia-Associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting a-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 17, 225-234 (2010
35. M. E. Figueroa, O. Abdel-Wahab, C. Lu, P. S. Ward, J. Patel, A. Shih, Y. Li, N. Bhagwat, A. Vasanthakumar, H. F. Fernandez, M. S. Tallman, Z. Sun, K. Wolniak, J. K. Peeters, W. Liu, S. E. Choe, V. R. Fantin, E. Paietta, B. Löwenberg, J. D. Licht, L. A. Godley, R. Delwel, P. J. Valk, C. B. Thompson, R. L. Levine, A. Melnick, Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 18, 553-567 (2010
36. C. Lu, P. S. Ward, G. S. Kapoor, D. Rohle, S. Turcan, O. Abdel-Wahab, C. R. Edwards, R. Khanin, M. E. Figueroa, A. Melnick, K. E. Wellen, D. M. O'Rourke, S. L. Berger, T. A. Chan, R. L. Levine, I. K. Mellinghoff, C. B. Thompson, IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 483, 474-478 (2012
37. J.-A. Losman, R. E. Looper, P. Koivunen, S. Lee, R. K. Schneider, C. McMahon, G. S. Cowley, D. E. Root, B. L. Ebert, W. G. Kaelin Jr., (R)-2-hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible. Science 339, 1621-1625 (2013
38. P. Koivunen, S. Lee, C. G. Duncan, G. Lopez, G. Lu, S. Ramkissoon, J. A. Losman, P. Joensuu, U. Bergmann, S. Gross, J. Travins, S. Weiss, R. Looper, K. L. Ligon, R. G. W. Verhaak, H. Yan, W. G. Kaelin Jr., Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation. Nature 483, 484-488 (2012
39. S. Turcan, D. Rohle, A. Goenka, L. A. Walsh, F. Fang, E. Yilmaz, C. Campos, A. W. M. Fabius, C. Lu, P. S. Ward, C. B. Thompson, A. Kaufman, O. Guryanova, R. Levine, A. Heguy, A. Viale, L. G. T. Morris, J. T. Huse, I. K. Mellinghoff, T. A. Chan, IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature 483, 479-483 (2012
40. R. Chowdhury, K. K. Yeoh, Y.-M. Tian, L. Hillringhaus, E. A. Bagg, N. R. Rose, I. K. H. Leung, X. S. Li, E. C. Y. Woon, M. Yang, M. A. McDonough, O. N. King, I. J. Clifton, R. J. Klose, T. D. W. Claridge, P. J. Ratcliffe, C. J. Schofield, A. Kawamura, The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases. EMBO Rep. 12, 463-469 (2011
41. W. Xu, H. Yang, Y. Liu, Y. Yang, P. Wang, S.-H. Kim, S. Ito, C. Yang, P. Wang, M.-T. Xiao, L.-X. Liu, W.-. Jiang, J. Liu, J.-. Zhang, B. Wang, S. Frye, Y. Zhang, Y.-. Xu, Q.-. Lei, K.-L. Guan, S.-. Zhao, Y. Xiong, Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of a-ketoglutarate-dependent dioxygenases. Cancer Cell 19, 17-30 (2011
42. A. M. Intlekofer, R. G. Dematteo, S. Venneti, L. W. S. Finley, C. Lu, A. R. Judkins, A. S. Rustenburg, P. B. Grinaway, J. D. Chodera, J. R. Cross, C. B. Thompson, Hypoxia induces production of L-2-hydroxyglutarate. Cell Metab. 22, 304-311 (2015
43. R. Rzem, M.-F. Vincent, E. Van Schaftingen, M. Veiga-da-Cunha, L-2-hydroxyglutaric aciduria, a defect of metabolite repair. J. Inherit. Metab. Dis. 30, 681-689 (2007
44. W. M. Oldham, C. B. Clish, Y. Yang, J. Loscalzo, Hypoxia-mediated increases in L-2-hydroxyglutarate coordinate the metabolic response to reductive stress. Cell Metab. 22, 291-303 (2015
45. M. Topçu, F. Jobard, S. Halliez, T. Coskun, C. Yalçinkayal, F. O. Gerceker, R. J. A. Wanders, J.-F. Prud'homme, M. Lathrop, M. Özguc, J. Fischer, L-2-Hydroxyglutaric aciduria: Identification of a mutant gene C14orf160, localized on chromosome 14q22.1. Hum. Mol. Genet. 13, 2803-2811 (2004
46. M. Aghili, F. Zahedi, E. Rafiee, Hydroxyglutaric aciduria and malignant brain tumor: A case report and literature review. J. Neurooncol 91, 233-236 (2009
47. A. R. Mullen, Z. Hu, X. Shi, L. Jiang, L. K. Boroughs, Z. Kovacs, R. Boriack, D. Rakheja, L. B. Sullivan, W. M. Linehan, N. S. Chandel, R. J. DeBerardinis, Oxidation of alphaketoglutarate is required for reductive carboxylation in cancer cells with mitochondrial defects. Cell Rep. 7, 1679-1690 (2014
48. E.-H. Shim, C. B. Livi, D. Rakheja, J. Tan, D. Benson, V. Parekh, E.-Y. Kho, A. P. Ghosh, R. Kirkman, S. Velu, S. Dutta, B. Chenna, S. L. Rea, R. J. Mishur, Q. Li, T. L. Johnson-Pais, L. Guo, S. Bae, S. Wei, K. Block, S. Sudarshan, L-2-Hydroxyglutarate: An epigenetic modifier and putative oncometabolite in renal cancer. Cancer Discov. 4, 1290-1298 (2014
49. I. P. M. Tomlinson, N. A. Alam, A. J. Rowan, E. Barclay, E. E. M. Jaeger, D. Kelsell, I. Leigh, P. Gorman, H. Lamlum, S. Rahman, R. R. Roylance, S. Olpin, S. Bevan, K. Barker, N. Hearle, R. S. Houlston, M. Kiuru, R. Lehtonen, A. Karhu, S. Vilkki, P. Laiho, C. Eklund, O. Vierimaa, K. Aittomäki, M. Hietala, P. Sistonen, A. Paetau, R. Salovaara, R. Herva, V. Launonen, L. A. Aaltonen; Multiple Leiomyoma Consortium, Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat. Genet. 30, 406-410 (2002
50. E. Gottlieb, I. P. M. Tomlinson, Mitochondrial tumour suppressors: A genetic and biochemical update. Nat. Rev. Cancer 5, 857-866 (2005
51. B. E. Baysal, R. E. Ferrell, J. E. Willett-Brozick, E. C. Lawrence, D. Myssiorek, A. Bosch, A. van der Mey, P. E. M. Taschner, W. S. Rubinstein, E. N. Myers, C. W. Richard III, C. J. Cornelisse, P. Devilee, B. Devlin, Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science 287, 848-851 (2000
52. T. Laukka, C. J. Mariani, T. Ihantola, J. Z. Cao, J. Hokkanen, W. G. Kaelin Jr., L. A. Godley, P. Koivunen, Fumarate and succinate regulate expression of hypoxia-inducible genes via TET enzymes. J. Biol. Chem. 291, 4256-4265 (2016
53. M. Xiao, H. Yang, W. Xu, S. Ma, H. Lin, H. Zhu, L. Liu, Y. Liu, C. Yang, Y. Xu, S. Zhao, D. Ye, Y. Xiong, K.-L. Guan, Inhibition of a-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors. Genes Dev. 26, 1326-1338 (2012
54. W. G. Kaelin Jr., S. L. McKnight, Influence of metabolism on epigenetics and disease. Cell 153, 56-69 (2013
55. L. B. Sullivan, E. Martinez-Garcia, H. Nguyen, A. R. Mullen, E. Dufour, S. Sudarshan, J. D. Licht, R. J. Deberardinis, N. S. Chandel, The proto-oncometabolite fumarate binds glutathione to amplify ROS-dependent signaling. Mol. Cell 51, 236-248 (2013).
56. J. Adam, E. Hatipoglu, L. O'Flaherty, N. Ternette, N. Sahgal, H. Lockstone, D. Baban, E. Nye, G. W. Stamp, K. Wolhuter, M. Stevens, R. Fischer, P. Carmeliet, P. H. Maxwell, C. W. Pugh, N. Frizzell, T. Soga, B. M. Kessler, M. El-Bahrawy, P. J. Ratcliffe, P. J. Pollard, Renal cyst formation in Fh1-deficient mice is independent of the Hif/Phd pathway: Roles for fumarate in KEAP1 succination and Nrf2 signaling. Cancer Cell 20, 524-537 (2011
57. C. Bardella, M. El-Bahrawy, N. Frizzell, J. Adam, N. Ternette, E. Hatipoglu, K. Howarth, L. O'Flaherty, I. Roberts, G. Turner, J. Taylor, K. Giaslakiotis, V. M. Macaulay, A. L. Harris, A. Chandra, H. J. Lehtonen, V. Launonen, L. A. Aaltonen, C. W. Pugh, R. Mihai, D. Trudgian, B. Kessler, J. W. Baynes, P. J. Ratcliffe, I. P. Tomlinson, P. J. Pollard, Aberrant succination of proteins in fumarate hydratase-deficient mice and HLRCC patients is a robust biomarker of mutation status. J. Pathol. 225, 4-11 (2011
58. A. Ooi, J.-C. Wong, D. Petillo, D. Roossien, V. Perrier-Trudova, D. Whitten, B. W. H. Min, M.-H. Tan, Z. Zhang, X. J. Yang, M. Zhou, B. Gardie, V. Molinié, S. Richard, P. H. Tan, B. T. Teh, K. A. Furge, An antioxidant response phenotype shared between hereditary and sporadic type 2 papillary renal cell carcinoma. Cancer Cell 20, 511-523 (2011
59. O. Warburg, On respiratory impairment in cancer cells. Science 124, 269-270 (1956
60. O. Warburg, On the origin of cancer cells. Science 123, 309-314 (1956
61. C. V. Dang, Links between metabolism and cancer. Genes Dev. 26, 877-890 (2012
62. W. J. Israelsen, T. L. Dayton, S. M. Davidson, B. P. Fiske, A. M. Hosios, G. Bellinger, J. Li, Y. Yu, M. Sasaki, J. W. Horner, L. N. Burga, J. Xie, M. J. Jurczak, R. A. DePinho, C. B. Clish, T. Jacks, R. G. Kibbey, G. M. Wulf, D. Di Vizio, G. B. Mills, L. C. Cantley, M. G. Vander Heiden, PKM2 isoform-specific deletion reveals a differential requirement for pyruvate kinase in tumor cells. Cell 155, 397-409 (2013
63. S. Joshi, D. Tolkunov, H. Aviv, A. A. Hakimi, M. Yao, J. J. Hsieh, S. Ganesan, C. S. Chan, E. White, The genomic landscape of renal oncocytoma identifies a metabolic barrier to tumorigenesis. Cell Rep. 13, 1895-1908 (2015
64. F. Weinberg, R. Hamanaka, W. W. Wheaton, S. Weinberg, J. Joseph, M. Lopez, B. Kalyanaraman, G. M. Mutlu, G. R. S. Budinger, N. S. Chandel, Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity. Proc. Natl. Acad. Sci. U.S.A. 107, 8788-8793 (2010
65. I. Martinez-Reyes, L. P. Diebold, H. Kong, M. Schieber, H. Huang, C. T. Hensley, M. M. Mehta, T. Wang, J. H. Santos, R. Woychik, E. Dufour, J. N. Spelbrink, S. E. Weinberg, Y. Zhao, R. J. DeBerardinis, N. S. Chandel, TCA cycle and mitochondrial membrane potential are necessary for diverse biological functions. Mol. Cell 61, 199-209 (2016
66. X. L. Zu, M. Guppy, Cancer metabolism: Facts, fantasy, and fiction. Biochem. Biophys. Res. Commun. 313, 459-465 (2004
67. C. Lussey-Lepoutre, K. E. R. Hollinshead, C. Ludwig, M. Menara, A. Morin, L.-J. Castro-Vega, S. J. Parker, M. Janin, C. Martinelli, C. Ottolenghi, C. Metallo, A.-P. Gimenez-Roqueplo, J. Favier, D. A. Tennant, Loss of succinate dehydrogenase activity results in dependency on pyruvate carboxylation for cellular anabolism. Nat. Commun. 6, 8784 (2015
68. S. Cardaci, L. Zheng, G. MacKay, N. J. F. van den Broek, E. D. MacKenzie, C. Nixon, D. Stevenson, S. Tumanov, V. Bulusu, J. J. Kamphorst, A. Vazquez, S. Fleming, F. Schiavi, G. Kalna, K. Blyth, D. Strathdee, E. Gottlieb, Pyruvate carboxylation enables growth of SDH-deficient cells by supporting aspartate biosynthesis. Nat. Cell Biol. 17, 1317-1326 (2015
69. A. R. Mullen, W. W. Wheaton, E. S. Jin, P.-H. Chen, L. B. Sullivan, T. Cheng, Y. Yang, W. M. Linehan, N. S. Chandel, R. J. DeBerardinis, Reductive carboxylation supports growth in tumour cells with defective mitochondria. Nature 481, 385-388 (2012
70. R. Guzy, B. Sharma, E. Bell, N. Chandel, P. Schumacker, Loss of the SdhB, but Not the SdhA, subunit of complex II triggers reactive oxygen species-dependent hypoxiainducible factor activation and tumorigenesis. Mol. Cell. Biol. 28, 718-731 (2008
71. C. T. Hensley, A. T. Wasti, R. J. DeBerardinis, Glutamine and cancer: Cell biology, physiology, and clinical opportunities. J. Clin. Invest. 123, 3678-3684 (2013
72. J. R. Mayers, C. Wu, C. B. Clish, P. Kraft, M. E. Torrence, B. P. Fiske, C. Yuan, Y. Bao, M. K. Townsend, S. S. Tworoger, S. M. Davidson, T. Papagiannakopoulos, A. Yang, T. L. Dayton, S. Ogino, M. J. Stampfer, E. L. Giovannucci, Z. R. Qian, D. A. Rubinson, J. Ma, H. D. Sesso, J. M. Gaziano, B. B. Cochrane, S. Liu, J. Wactawski-Wende, J. E. Manson, M. N. Pollak, A. C. Kimmelman, A. Souza, K. Pierce, T. J. Wang, R. E. Gerszten, C. S. Fuchs, M. G. Vander Heiden, B. M. Wolpin, Elevation of circulating branched-chain amino acids is an early event in human pancreatic adenocarcinoma development. Nat. Med. 20, 1193-1198 (2014
73. N. Chandel, G. R. S. Budinger, S. H. Choe, P. T. Schumacker, Cellular respiration during hypoxia. Role of cytochrome oxidase as the oxygen sensor in hepatocytes. J. Biol. Chem. 272, 18808-18816 (1997
74. J. Fan, J. J. Kamphorst, R. Mathew, M. K. Chung, E. White, T. Shlomi, J. D. Rabinowitz, Glutamine-driven oxidative phosphorylation is a major ATP source in transformed mammalian cells in both normoxia and hypoxia. Mol. Syst. Biol. 9, 712 (2013
75. A. Le, A. N. Lane, M. Hamaker, S. Bose, A. Gouw, J. Barbi, T. Tsukamoto, C. J. Rojas, B. S. Slusher, H. Zhang, L. J. Zimmerman, D. C. Liebler, R. J. C. Slebos, P. K. Lorkiewicz, R. M. Higashi, T. W. M. Fan, C. V. Dang, Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells. Cell Metab. 15, 110-121 (2012
76. A. Le, Z. E. Stine, C. Nguyen, J. Afzal, P. Sun, M. Hamaker, N. M. Siegel, A. M. Gouw, B.-h. Kang, S.-H. Yu, R. L. Cochran, K. A. Sailor, H. Song, C. V. Dang, Tumorigenicity of hypoxic respiring cancer cells revealed by a hypoxia-cell cycle dual reporter. Proc. Natl. Acad. Sci. U.S.A. 111, 12486-12491 (2014
77. J. J. Kamphorst, M. Nofal, C. Commisso, S. R. Hackett, W. Lu, E. Grabocka, M. G. Vander Heiden, G. Miller, J. A. Drebin, D. Bar-Sagi, C. B. Thompson, J. D. Rabinowitz, Human pancreatic cancer tumors are nutrient poor and tumor cells actively scavenge extracellular protein. Cancer Res. 75, 544-553 (2015
78. C. M. Metallo, P. A. Gameiro, E. L. Bell, K. R. Mattaini, J. Yang, K. Hiller, C. M. Jewell, Z. R. Johnson, D. J. Irvine, L. Guarente, J. K. Kelleher, M. G. Vander Heiden, O. Iliopoulos, G. Stephanopoulos, Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature 481, 380-384 (2012
79. D. R. Wise, P. S. Ward, J. E. S. Shay, J. R. Cross, J. J. Gruber, U. M. Sachdeva, J. M. Platt, R. G. DeMatteo, M. C. Simon, C. B. Thompson, Hypoxia promotes isocitrate dehydrogenasedependent carboxylation of a-ketoglutarate to citrate to support cell growth and viability. Proc. Natl. Acad. Sci. U.S.A. 108, 19611-19616 (2011
80. M. Laplante, D. M. Sabatini, mTOR signaling in growth control and disease. Cell 149, 274-293 (2012
81. J. Y. Guo, H.-Y. Chen, R. Mathew, J. Fan, A. M. Strohecker, G. Karsli-Uzunbas, J. J. Kamphorst, G. Chen, J. M. S. Lemons, V. Karantza, H. A. Coller, R. S. DiPaola, C. Gelinas, J. D. Rabinowitz, E. White, Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis. Genes Dev. 25, 460-470 (2011
82. A. M. Strohecker, E. White, Autophagy promotes BrafV600E-driven lung tumorigenesis by preserving mitochondrial metabolism. Autophagy 10, 384-385 (2014
83. N. J. Lanning, B. D. Looyenga, A. L. Kauffman, N. M. Niemi, J. Sudderth, R. J. DeBerardinis, J. P. MacKeigan, A mitochondrial RNAi screen defines cellular bioenergetic determinants and identifies an adenylate kinase as a key regulator of ATP levels. Cell Rep. 7, 907-917 (2014
84. D. G. Hardie, B. E. Schaffer, A. Brunet, AMPK: An energy-sensing pathway with multiple inputs and outputs. Trends Cell Biol. 26, 190-201 (2016
85. J. J. Kamphorst, J. R. Cross, J. Fan, E. de Stanchina, R. Mathew, E. P. White, C. B. Thompson, J. D. Rabinowitz, Hypoxic and Ras-Transformed cells support growth by scavenging unsaturated fatty acids fromlysophospholipids. Proc. Natl. Acad. Sci. U.S.A. 110, 8882-8887 (2013
86. K. M. Nieman, H. A. Kenny, C. V. Penicka, A. Ladanyi, R. Buell-Gutbrod, M. R. Zillhardt, I. L. Romero, M. S. Carey, G. B. Mills, G. S. Hotamisligil, S. D. Yamada, M. E. Peter, K. Gwin, E. Lengyel, Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nat. Med. 17, 1498-1503 (2011
87. A. N. McCracken, A. L. Edinger, Nutrient transporters: The Achilles' heel of anabolism. Trends Endocrinol. Metab. 24, 200-208 (2013
88. P. Nicklin, P. Bergman, B. Zhang, E. Triantafellow, H. Wang, B. Nyfeler, H. Yang, M. Hild, C. Kung, C. Wilson, V. E. Myer, J. P. MacKeigan, J. A. Porter, Y. K. Wang, L. C. Cantley, P. M. Finan, L. O. Murphy, Bidirectional transport of amino acids regulates mTOR and autophagy. Cell 136, 521-534 (2009
89. L. Galluzzi, F. Pietrocola, B. Levine, G. Kroemer, Metabolic control of autophagy. Cell 159, 1263-1276 (2014
90. E. White, The role for autophagy in cancer. J. Clin. Invest. 125, 42-46 (2015
91. L. Galluzzi, F. Pietrocola, J. M. Bravo-San Pedro, R. K. Amaravadi, E. H. Baehrecke, F. Cecconi, P. Codogno, J. Debnath, D. A. Gewirtz, V. Karantza, A. Kimmelman, S. Kumar, B. Levine, M. C. Maiuri, S. J. Martin, J. Penninger, M. Piacentini, D. C. Rubinsztein, H.-U. Simon, A. Simonsen, A. M. Thorburn, G. Velasco, K. M. Ryan, G. Kroemer, Autophagy in malignant transformation and cancer progression. EMBO J. 34, 856-880 (2015
92. C. Commisso, S. M. Davidson, R. G. Soydaner-Azeloglu, S. J. Parker, J. J. Kamphorst, S. Hackett, E. Grabocka, M. Nofal, J. A. Drebin, C. B. Thompson, J. D. Rabinowitz, C. M. Metallo, M. G. Vander Heiden, D. Bar-Sagi, Macropinocytosis of protein is an amino acid supply route in Ras-Transformed cells. Nature 497, 633-637 (2013
93. W. Palm, Y. Park, K. Wright, N. N. Pavlova, D. A. Tuveson, C. B. Thompson, The utilization of extracellular proteins as nutrients is suppressed by mTORC1. Cell 162, 259-270 (2015
94. H. Yoo, G. Stephanopoulos, J. K. Kelleher, Quantifying carbon sources for de novo lipogenesis in wild-Type and IRS-1 knockout brown adipocytes. J. Lipid Res. 45, 1324-1332 (2004
95. R. J. DeBerardinis, A. Mancuso, E. Daikhin, I. Nissim, M. Yudkoff, S. Wehrli, C. B. Thompson, 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 (2007
96. Z. T. Schug, B. Peck, D. T. Jones, Q. Zhang, S. Grosskurth, I. S. Alam, L. M. Goodwin, E. Smethurst, S. Mason, K. Blyth, L. McGarry, D. James, E. Shanks, G. Kalna, R. E. Saunders, M. Jiang, M. Howell, F. Lassailly, M. Z. Thin, B. Spencer-Dene, G. Stamp, N. J. F. van den Broek, G. Mackay, V. Bulusu, J. J. Kamphorst, S. Tardito, D. Strachan, A. L. Harris, E. O. Aboagye, S. E. Critchlow, M. J. O. Wakelam, A. Schulze, E. Gottlieb, Acetyl-CoA synthetase 2 promotes acetate utilization and maintains cancer cell growth under metabolic stress. Cancer Cell 27, 57-71 (2015
97. C. R. Green, M. Wallace, A. S. Divakaruni, S. A. Phillips, A. N. Murphy, T. P. Ciaraldi, C. M. Metallo, Branched-chain amino acid catabolism fuels adipocyte differentiation and lipogenesis. Nat. Chem. Biol. 12, 15-21 (2016
98. R. Kannan, I. Lyon, N. Baker, Dietary control of lipogenesis in vivo in host tissues and tumors of mice bearing Ehrlich ascites carcinoma. Cancer Res. 40, 4606-4611 (1980
99. M. Ookhtens, R. Kannan, I. Lyon, N. Baker, Liver and adipose tissue contributions to newly formed fatty acids in an ascites tumor. Am. J. Physiol. 247, R146-R153 (1984
100. J. Fan, J. Ye, J. J. Kamphorst, T. Shlomi, C. B. Thompson, J. D. Rabinowitz, Quantitative flux analysis reveals folate-dependent NADPH production. Nature 510, 298-302 (2014
101. C. A. Lewis, S. J. Parker, B. P. Fiske, D. McCloskey, D. Y. Gui, C. R. Green, N. I. Vokes, A. M. Feist, M. G. Vander Heiden, C. M. Metallo, Tracing compartmentalized NADPH metabolism in the cytosol and mitochondria of mammalian cells. Mol. Cell 55, 253-263 (2014
102. J. D. Horton, J. L. Goldstein, M. S. Brown, SREBPs: Activators of the complete program of cholesterol and fatty acid synthesis in the liver. J. Clin. Invest. 109, 1125-1131 (2002
103. K. Düvel, J. L. Yecies, S. Menon, P. Raman, A. I. Lipovsky, A. L. Souza, E. Triantafellow, Q. Ma, R. Gorski, S. Cleaver, M. G. Vander Heiden, J. P. MacKeigan, P. M. Finan, C. B. Clish, L. O. Murphy, B. D. Manning, Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol. Cell 39, 171-183 (2010
104. J. L. Goldstein, R. A. DeBose-Boyd, M. S. Brown, Protein sensors for membrane sterols. Cell 124, 35-46 (2006
105. T. R. Peterson, S. S. Sengupta, T. E. Harris, A. E. Carmack, S. A. Kang, E. Balderas, D. A. Guertin, K. L. Madden, A. E. Carpenter, B. N. Finck, D. M. Sabatini, mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway. Cell 146, 408-420 (2011
106. R. J. Deberardinis, J. J. Lum, C. B. Thompson, Phosphatidylinositol 3-kinase-dependent modulation of carnitine palmitoyltransferase 1A expression regulates lipid metabolism during hematopoietic cell growth. J. Biol. Chem. 281, 37372-37380 (2006
107. R. M. Young, D. Ackerman, Z. L. Quinn, A. Mancuso, M. Gruber, L. Liu, D. N. Giannoukos, E. Bobrovnikova-Marjon, J. A. Diehl, B. Keith, M. C. Simon, Dysregulated mTORC1 renders cells critically dependent on desaturated lipids for survival under tumor-like stress. Genes Dev. 27, 1115-1131 (2013
108. C. Yokoyama, X. Wang, M. R. Briggs, A. Admon, J. Wu, X. Hua, J. L. Goldstein, M. S. Brown, SREBP-1, a basic-helix-loop-helix-leucine zipper protein that controls transcription of the low density lipoprotein receptor gene. Cell 75, 187-197 (1993
109. D. Guo, R. M. Prins, J. Dang, D. Kuga, A. Iwanami, H. Soto, K. Y. Lin, T. T. Huang, D. Akhavan, M. B. Hock, S. Zhu, A. A. Kofman, S. J. Bensinger, W. H. Yong, H. V. Vinters, S. Horvath, A. D. Watson, J. G. Kuhn, H. I. Robins, M. P. Mehta, P. Y. Wen, L. M. DeAngelis, M. D. Prados, I. K. Mellinghoff, T. F. Cloughesy, P. S. Mischel, EGFR signaling through an Akt-SREBP-1-dependent, rapamycin-resistant pathway sensitizes glioblastomas to antilipogenic therapy. Sci. Signal. 2, ra82 (2009
110. D. Guo, F. Reinitz, M. Youssef, C. Hong, D. Nathanson, D. Akhavan, D. Kuga, A. N. Amzajerdi, H. Soto, S. Zhu, I. Babic, K. Tanaka, J. Dang, A. Iwanami, B. Gini, J. DeJesus, D. D. Lisiero, T. T. Huang, R. M. Prins, P. Y. Wen, H. I. Robins, M. D. Prados, L. M. DeAngelis, I. K. Mellinghoff, M. P. Mehta, C. D. James, A. Chakravarti, T. F. Cloughesy, P. Tontonoz, P. S. Mischel, An LXR agonist promotes glioblastoma cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway. Cancer Discov. 1, 442-456 (2011
111. A. Stincone, A. Prigione, T. Cramer, M. M. C. Wamelink, K. Campbell, E. Cheung, V. Olin-Sandoval, N.-M. Grüning, A. Krüger, M. Tauqeer Alam, M. A. Keller, M. Breitenbach, K. M. Brindle, J. D. Rabinowitz, M. Ralser, The return of metabolism: Biochemistry and physiology of the pentose phosphate pathway. Biol. Rev. Camb. Philos. Soc. 90, 927-963 (2014
112. M. G. Vander Heiden, Targeting cancer metabolism: A therapeutic window opens. Nat. Rev. Drug Discov. 10, 671-684 (2011
113. I. Ben-Sahra, J. J. Howell, J. M. Asara, B. D. Manning, Stimulation of de novo pyrimidine synthesis by growth signaling through mTOR and S6K1. Science 339, 1323-1328 (2013
114. M. P. Murphy, How mitochondria produce reactive oxygen species. Biochem. J. 417, 1-13 (2009
115. M. D. Brand, The sites and topology of mitochondrial superoxide production. Exp. Gerontol. 45, 466-472 (2010
116. S. G. Rhee, H. A. Woo, I. S. Kil, S. H. Bae, Peroxiredoxin functions as a peroxidase and a regulator and sensor of local peroxides. J. Biol. Chem. 287, 4403-4410 (2012
117. A. G. Cox, C. C. Winterbourn, M. B. Hampton, Mitochondrial peroxiredoxin involvement in antioxidant defence and redox signalling. Biochem. J. 425, 313-325 (2010
118. M. P. Murphy, Mitochondrial thiols in antioxidant protection and redox signaling: Distinct roles for glutathionylation and other thiol modifications. Antioxid. Redox Signal. 16, 476-495 (2012
119. T. Finkel, From sulfenylation to sulfhydration: What a thiolate needs to tolerate. Sci. Signal. 5, pe10 (2012
120. E. C. Cheung, P. Lee, F. Ceteci, C. Nixon, K. Blyth, O. J. Sansom, K. H. Vousden, Opposing effects of TIGAR- And RAC1-derived ROS on Wnt-driven proliferation in the mouse intestine. Genes Dev. 30, 52-63 (2016
121. K. Irani, Y. Xia, J. L. Zweier, S. J. Sollott, C. J. Der, E. R. Fearon, M. Sundaresan, T. Finkel, P. J. Goldschmidt-Clermont, Mitogenic signaling mediated by oxidants in Rastransformed fibroblasts. Science 275, 1649-1652 (1997
122. N. S. Chandel, E. Maltepe, E. Goldwasser, C. E. Mathieu, M. C. Simon, P. T. Schumacker, Mitochondrial reactive oxygen species trigger hypoxia-induced transcription. Proc. Natl. Acad. Sci. U.S.A. 95, 11715-11720 (1998
123. A. L. Orr, L. Vargas, C. N. Turk, J. E. Baaten, J. T. Matzen, V. J. Dardov, S. J. Attle, J. Li, D. C. Quackenbush, R. L. S. Goncalves, I. V. Perevoshchikova, H. M. Petrassi, S. L. Meeusen, E. K. Ainscow, M. D. Brand, Suppressors of superoxide production from mitochondrial complex III. Nat. Chem. Biol. 11, 834-836 (2015
124. P. E. Porporato, V. L. Payen, J. Pérez-Escuredo, C. J. De Saedeleer, P. Danhier, T. Copetti, S. Dhup, M. Tardy, T. Vazeille, C. Bouzin, O. Feron, C. Michiels, B. Gallez, P. Sonveaux, A mitochondrial switch promotes tumor metastasis. Cell Rep. 8, 754-766 (2014
125. J. M. Munson, L. Fried, S. A. Rowson, M. Y. Bonner, L. Karumbaiah, B. Diaz, S. A. Courtneidge, U. G. Knaus, D. J. Brat, J. L. Arbiser, R. V. Bellamkonda, Anti-invasive adjuvant therapy with imipramine blue enhances chemotherapeutic efficacy against glioma. Sci. Transl. Med. 4, 127ra36 (2012
126. N. S. Chandel, D. A. Tuveson, The promise and perils of antioxidants for cancer patients. N. Engl. J. Med. 371, 177-178 (2014
127. M. C. Jaramillo, D. D. Zhang, The emerging role of the Nrf2-Keap1 signaling pathway in cancer. Genes Dev. 27, 2179-2191 (2013
128. G. M. DeNicola, F. A. Karreth, T. J. Humpton, A. Gopinathan, C. Wei, K. Frese, D. Mangal, K. H. Yu, C. J. Yeo, E. S. Calhoun, F. Scrimieri, J.M. Winter, R. H. Hruban, C. Iacobuzio-Donahue, S. E. Kern, I. A. Blair, D. A. Tuveson, Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature 475, 106-109 (2011
129. G. M. DeNicola, P.-H. Chen, E. Mullarky, J. A. Sudderth, Z. Hu, D. Wu, H. Tang, Y. Xie, J. M. Asara, K. E. Huffman, I. I. Wistuba, J. D. Minna, R. J. DeBerardinis, L. C. Cantley, NRF2 regulates serine biosynthesis in non-small cell lung cancer. Nat. Genet. 47, 1475-1481 (2015
130. J. Ye, J. Fan, S. Venneti, Y.-W. Wan, B. R. Pawel, J. Zhang, L. W. S. Finley, C. Lu, T. Lindsten, J. R. Cross, G. Qing, Z. Liu, M. C. Simon, J. D. Rabinowitz, C. B. Thompson, Serine catabolism regulates mitochondrial redox control during hypoxia. Cancer Discov. 4, 1406-1417 (2014
131. I. S. Harris, A. E. Treloar, S. Inoue, M. Sasaki, C. Gorrini, K. C. Lee, K. Y. Yung, D. Brenner, C. B. Knobbe-Thomsen, M. A. Cox, A. Elia, T. Berger, D. W. Cescon, A. Adeoye, A. Brüstle, S. D. Molyneux, J. M. Mason, W. Y. Li, K. Yamamoto, A. Wakeham, H. K. Berman, R. Khokha, S. J. Done, T. J. Kavanagh, C.-W. Lam, T. W. Mak, Glutathione and thioredoxin antioxidant pathways synergize to drive cancer initiation and progression. Cancer Cell 27, 211-222 (2015
132. D. J. Garama, T. J. Harris, C. L. White, F. J. Rossello, M. Abdul-Hay, D. J. Gough, D. E. Levy, A synthetic lethal interaction between glutathione synthesis and mitochondrial reactive oxygen species provides a tumor-specific vulnerability dependent on STAT3. Mol. Cell. Biol. 35, 3646-3656 (2015
133. C. Gorrini, I. S. Harris, T. W. Mak, Modulation of oxidative stress as an anticancer strategy. Nat. Rev. Drug Discov. 12, 931-947 (2013
134. Y. Saito, R. H. Chapple, A. Lin, A. Kitano, D. Nakada, AMPK protects leukemia-initiating cells in myeloid leukemias from metabolic stress in the bone marrow. Cell Stem Cell 17, 585-596 (2015
135. S.-M. Jeon, N. S. Chandel, N. Hay, AMPK regulates NADPH homeostasis to promote tumour cell survival during energy stress. Nature 485, 661-665 (2012
136. V. S. LeBleu, J. T. O'Connell, K. N. Gonzalez Herrera, H. Wikman, K. Pantel, M. C. Haigis, F. M. de Carvalho, A. Damascena, L. T. Domingos Chinen, R. M. Rocha, J. M. Asara, R. Kalluri, PGC-1a mediates mitochondrial biogenesis and oxidative phosphorylation in cancer cells to promote metastasis. Nat. Cell Biol. 16, 992-1003 (2014
137. Z. T. Schafer, A. R. Grassian, L. Song, Z. Jiang, Z. Gerhart-Hines, H. Y. Irie, S. Gao, P. Puigserver, J. S. Brugge, Antioxidant and oncogene rescue of metabolic defects caused by loss of matrix attachment. Nature 461, 109-113 (2009
138. L. Jiang, A. A. Shestov, P. Swain, C. Yang, S. J. Parker, Q. A. Wang, L. S. Terada, N. D. Adams, M. T. McCabe, B. Pietrak, S. Schmidt, C. M. Metallo, B. P. Dranka, B. Schwartz, R. J. DeBerardinis, Reductive carboxylation supports redox homeostasis during anchorageindependent growth. Nature 532, 255-258 (2016
139. A. Erez, R. J. DeBerardinis, Metabolic dysregulation in monogenic disorders and cancer- Finding method in madness. Nat. Rev. Cancer 15, 440-448 (2015
140. E. L. Pearce, M. C. Poffenberger, C.-H. Chang, R. G. Jones, Fueling immunity: Insights into metabolism and lymphocyte function. Science 342, 1242454 (2013
141. K. Ito, T. Suda, Metabolic requirements for the maintenance of self-renewing stem cells. Nat. Rev. Mol. Cell Biol. 15, 243-256 (2014
142. H. Shim, C. Dolde, B. C. Lewis, C.-S. Wu, G. Dang, R. A. Jungmann, R. Dalla-Favera, C. V. Dang, c-Myc transactivation of LDH-A: Implications for tumor metabolism and growth. Proc. Natl. Acad. Sci. U.S.A. 94, 6658-6663 (1997
143. V. R. Fantin, J. St-Pierre, P. Leder, Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance. Cancer Cell 9, 425-434 (2006
144. A. Le, C. R. Cooper, A. M. Gouw, R. Dinavahi, A. Maitra, L. M. Deck, R. E. Royer, D. L. Vander Jagt, G. L. Semenza, C. V. Dang, Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression. Proc. Natl. Acad. Sci. U.S.A. 107, 2037-2042 (2010
145. H. Xie, J.-. Hanai, J.-G. Ren, L. Kats, K. Burgess, P. Bhargava, S. Signoretti, J. Billiard, K. J. Duffy, A. Grant, X. Wang, P. K. Lorkiewicz, S. Schatzman, M. Bousamra II, A. N. Lane, R. M. Higashi, T. W. M. Fan, P. P. Pandolfi, V. P. Sukhatme, P. Seth, Targeting lactate dehydrogenase-A inhibits tumorigenesis and tumor progression in mouse models of lung cancer and impacts tumor-initiating cells. Cell Metab. 19, 795-809 (2014
146. Y.-H. Wang, W. J. Israelsen, D. Lee, V. W. C. Yu, N. T. Jeanson, C. B. Clish, L. C. Cantley, M. G. Vander Heiden, D. T. Scadden, Cell-state-specific metabolic dependency in hematopoiesis and leukemogenesis. Cell 158, 1309-1323 (2014
147. R. Haas, J. Smith, V. Rocher-Ros, S. Nadkarni, T. Montero-Melendez, F. D'Acquisto, E. J. Bland, M. Bombardieri, C. Pitzalis, M. Perretti, F. M. Marelli-Berg, C. Mauro, Lactate regulates metabolic and pro-inflammatory circuits in control of T cell migration and effector functions. PLOS Biol. 13, e1002202 (2015
148. O. R. Colegio, N.-Q. Chu, A. L. Szabo, T. Chu, A. M. Rhebergen, V. Jairam, N. Cyrus, C. E. Brokowski, S. C. Eisenbarth, G. M. Phillips, G. W. Cline, A. J. Phillips, R. Medzhitov, Functional polarization of tumour-Associated macrophages by tumour-derived lactic acid. Nature 513, 559-563 (2014
149. O. D. K. Maddocks, C. R. Berkers, S. M. Mason, L. Zheng, K. Blyth, E. Gottlieb, K. H. Vousden, Serine starvation induces stress and p53-dependent metabolic remodelling in cancer cells. Nature 493, 542-546 (2013
150. C. F. Labuschagne, N. J. F. van den Broek, G. M. Mackay, K. H. Vousden, O. D. K. Maddocks, Serine, but not glycine, supports one-carbon metabolism and proliferation of cancer cells. Cell Rep. 7, 1248-1258 (2014
151. D. Kim, B. P. Fiske, K. Birsoy, E. Freinkman, K. Kami, R. L. Possemato, Y. Chudnovsky, M. E. Pacold, W. W. Chen, J. R. Cantor, L. M. Shelton, D. Y. Gui, M. Kwon, S. H. Ramkissoon, K. L. Ligon, S. W. Kang, M. Snuderl, M. G. Vander Heiden, D. M. Sabatini, SHMT2 drives glioma cell survival in ischaemia but imposes a dependence on glycine clearance. Nature 520, 363-367 (2015
152. R. Nilsson, M. Jain, N. Madhusudhan, N. G. Sheppard, L. Strittmatter, C. Kampf, J. Huang, A. Asplund, V. K. Mootha, Metabolic enzyme expression highlights a key role for MTHFD2 and the mitochondrial folate pathway in cancer. Nat. Commun. 5, 3128 (2014
153. S. E. Weinberg, N. S. Chandel, Targeting mitochondria metabolism for cancer therapy. Nat. Chem. Biol. 11, 9-15 (2015
154. J. M. M. Evans, L. A. Donnelly, A. M. Emslie-Smith, D. R. Alessi, A. D. Morris, Metformin and reduced risk of cancer in diabetic patients. BMJ 330, 1304-1305 (2005
155. M. Buzzai, R. G. Jones, R. K. Amaravadi, J. J. Lum, R. J. DeBerardinis, F. Zhao, B. Viollet, C. B. Thompson, Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth. Cancer Res. 67, 6745-6752 (2007
156. R. M. Memmott, J. R. Mercado, C. R. Maier, S. Kawabata, S. D. Fox, P. A. Dennis, Metformin prevents tobacco carcinogen-induced lung tumorigenesis. Cancer Prev. Res. 3, 1066-1076 (2010
157. A. Tomimoto, H. Endo, M. Sugiyama, T. Fujisawa, K. Hosono, H. Takahashi, N. Nakajima, Y. Nagashima, K. Wada, H. Nakagama, A. Nakajima, Metformin suppresses intestinal polyp growth in ApcMin/+ mice. Cancer Sci. 99, 2136-2141 (2008
158. H. R. Bridges, A. J. Y. Jones, M. N. Pollak, J. Hirst, Effects of metformin and other biguanides on oxidative phosphorylation in mitochondria. Biochem. J. 462, 475-487 (2014
159. M.-Y. El-Mir, V. Nogueira, E. Fontaine, N. Avéret, M. Rigoulet, X. Leverve, Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J. Biol. Chem. 275, 223-228 (2000
160. M. R. Owen, E. Doran, A. P. Halestrap, Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem. J. 348 (Pt. 3), 607-614 (2000
161. W. W. Wheaton, S. E. Weinberg, R. B. Hamanaka, S. Soberanes, L. B. Sullivan, E. Anso, A. Glasauer, E. Dufour, G. M. Mutlu, G. R. S. Budigner, N. S. Chandel, Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis. Elife 3, e02242 (2014
162. T. Griss, E. E. Vincent, R. Egnatchik, J. Chen, E. H. Ma, B. Faubert, B. Viollet, R. J. DeBerardinis, R. G. Jones, Metformin antagonizes cancer cell proliferation by suppressing mitochondrial-dependent biosynthesis. PLOS Biol. 13, e1002309 (2015
163. A. Emami Riedmaier, P. Fisel, A. T. Nies, E. Schaeffeler, M. Schwab, Metformin and cancer: From the old medicine cabinet to pharmacological pitfalls and prospects. Trends Pharmacol. Sci. 34, 126-135 (2013
164. M. Pollak, Overcoming drug development bottlenecks with repurposing: Repurposing biguanides to target energy metabolism for cancer treatment. Nat. Med. 20, 591-593 (2014
165. K. Birsoy, R. Possemato, F. K. Lorbeer, E. C. Bayraktar, P. Thiru, B. Yucel, T. Wang, W. W. Chen, C. B. Clish, D. M. Sabatini, Metabolic determinants of cancer cell sensitivity to glucose limitation and biguanides. Nature 508, 108-112 (2014
166. D. B. Shackelford, E. Abt, L. Gerken, D. S. Vasquez, A. Seki, M. Leblanc, L. Wei, M. C. Fishbein, J. Czernin, P. S. Mischel, R. J. Shaw, LKB1 inactivation dictates therapeutic response of non-small cell lung cancer to the metabolism drug phenformin. Cancer Cell 23, 143-158 (2013
167. S.-P. Gravel, L. Hulea, N. Toban, E. Birman, M.-J. Blouin, M. Zakikhani, Y. Zhao, I. Topisirovic, J. St-Pierre, M. Pollak, Serine deprivation enhances antineoplastic activity of biguanides. Cancer Res. 74, 7521-7533 (2014
168. G. Karsli-Uzunbas, J. Y. Guo, S. Price, X. Teng, S. V. Laddha, S. Khor, N. Y. Kalaany, T. Jacks, C. S. Chan, J. D. Rabinowitz, E. White, Autophagy is required for glucose homeostasis and lung tumor maintenance. Cancer Discov. 4, 914-927 (2014
169. J. Son, C. A. Lyssiotis, H. Ying, X. Wang, S. Hua, M. Ligorio, R. M. Perera, C. R. Ferrone, E. Mullarky, N. Shyh-Chang, Y. Kang, J. B. Fleming, N. Bardeesy, J. M. Asara, M. C. Haigis, R. A. DePinho, L. C. Cantley, A. C. Kimmelman, Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature 496, 101-105 (2013
170. Y. Xiang, Z. E. Stine, J. Xia, Y. Lu, R. S. O'Connor, B. J. Altman, A. L. Hsieh, A. M. Gouw, A. G. Thomas, P. Gao, L. Sun, L. Song, B. Yan, B. S. Slusher, J. Zhuo, L. L. Ooi, C. G. L. Lee, A. Mancuso, A. S. McCallion, A. Le, M. C. Milone, S. Rayport, D. W. Felsher, C. V. Dang, Targeted inhibition of tumor-specific glutaminase diminishes cell-Autonomous tumorigenesis. J. Clin. Invest. 125, 2293-2306 (2015
171. S. A. Comerford, Z. Huang, X. Du, Y. Wang, L. Cai, A. K. Witkiewicz, H. Walters, M. N. Tantawy, A. Fu, H. C. Manning, J. D. Horton, R. E. Hammer, S. L. McKnight, B. P. Tu, Acetate dependence of tumors. Cell 159, 1591-1602 (2014
172. T. Mashimo, K. Pichumani, V. Vemireddy, K. J. Hatanpaa, D. K. Singh, S. Sirasanagandla, S. Nannepaga, S. G. Piccirillo, Z. Kovacs, C. Foong, Z. Huang, S. Barnett, B. E. Mickey, R. J. DeBerardinis, B. P. Tu, E. A. Maher, R. M. Bachoo, Acetate is a bioenergetic substrate for human glioblastoma and brain metastases. Cell 159, 1603-1614 (2014
173. J. A. Engelman, L. Chen, X. Tan, K. Crosby, A. R. Guimaraes, R. Upadhyay, M. Maira, K. McNamara, S. A. Perera, Y. Song, L. R. Chirieac, R. Kaur, A. Lightbown, J. Simendinger, T. Li, R. F. Padera, C. García-Echeverría, R. Weissleder, U. Mahmood, L. C. Cantley, K.-K. Wong, Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat. Med. 14, 1351-1356 (2008
174. D. Herranz, A. Ambesi-Impiombato, J. Sudderth, M. Sánchez-Martín, L. Belver, V. Tosello, L. Xu, A. A. Wendorff, M. Castillo, J. E. Haydu, J. Márquez, J. M. Matés, A. L. Kung, S. Rayport, C. Cordon-Cardo, R. J. DeBerardinis, A. A. Ferrando, Metabolic reprogramming induces resistance to anti-NOTCH1 therapies in T cell acute lymphoblastic leukemia. Nat. Med. 21, 1182-1189 (2015
175. A. Viale, P. Pettazzoni, C. A. Lyssiotis, H. Ying, N. Sánchez, M. Marchesini, A. Carugo, T. Green, S. Seth, V. Giuliani, M. Kost-Alimova, F. Muller, S. Colla, L. Nezi, G. Genovese, A. K. Deem, A. Kapoor, W. Yao, E. Brunetto, Y. Kang, M. Yuan, J. M. Asara, Y. A. Wang, T. P. Heffernan, A. C. Kimmelman, H. Wang, J. B. Fleming, L. C. Cantley, R. A. DePinho, G. F. Draetta, Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function. Nature 514, 628-632 (2014
176. P. Yuan, K. Ito, R. Perez-Lorenzo, C. Del Guzzo, J. H. Lee, C.-H. Shen, M. W. Bosenberg, M. McMahon, L. C. Cantley, B. Zheng, Phenformin enhances the therapeutic benefit of BRAFV600E inhibition in melanoma. Proc. Natl. Acad. Sci. U.S.A. 110, 18226-18231 (2013
177. A. Roesch, A. Vultur, I. Bogeski, H. Wang, K. M. Zimmermann, D. Speicher, C. Körbel, M. W. Laschke, P. A. Gimotty, S. E. Philipp, E. Krause, S. Pätzold, J. Villanueva, C. Krepler, M. Fukunaga-Kalabis, M. Hoth, B. C. Bastian, T. Vogt, M. Herlyn, Overcoming intrinsicmultidrug resistance in melanoma by blocking the mitochondrial respiratory chain of slow-cycling JARID1Bhigh cells. Cancer Cell 23, 811-825 (2013
178. A. Janzer, N. J. German, K. N. Gonzalez-Herrera, J. M. Asara, M. C. Haigis, K. Struhl, Metformin and phenformin deplete tricarboxylic acid cycle and glycolytic intermediates during cell transformation and NTPs in cancer stem cells. Proc. Natl. Acad. Sci. U.S.A. 111, 10574-10579 (2014
179. J. Yun, E. Mullarky, C. Lu, K. N. Bosch, A. Kavalier, K. Rivera, J. Roper, I. I. C. Chio, E. G. Giannopoulou, C. Rago, A. Muley, J. M. Asara, J. Paik, O. Elemento, Z. Chen, D. J. Pappin, L. E. Dow, N. Papadopoulos, S. S. Gross, L. C. Cantley, Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH. Science 350, 1391-1396 (2015
180. Q. Chen, M. G. Espey, A. Y. Sun, C. Pooput, K. L. Kirk, M. C. Krishna, D. B. Khosh, J. Drisko, M. Levine, Pharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenografts in mice. Proc. Natl. Acad. Sci. U.S.A. 105, 11105-11109 (2008
181. Y. Ma, J. Chapman, M. Levine, K. Polireddy, J. Drisko, Q. Chen, High-dose parenteral ascorbate enhanced chemosensitivity of ovarian cancer and reduced toxicity of chemotherapy. Sci. Transl. Med. 6, 222ra18 (2014
182. A. Tagde, H. Singh, M. H. Kang, C. P. Reynolds, The glutathione synthesis inhibitor buthionine sulfoximine synergistically enhanced melphalan activity against preclinical models of multiple myeloma. Blood Cancer J. 4, e229 (2014
183. A. Glasauer, L. A. Sena, L. P. Diebold, A. P. Mazar, N. S. Chandel, Targeting SOD1 reduces experimental non-small-cell lung cancer. J. Clin. Invest. 124, 117-128 (2014
184. O. Oivares, J. H. M. Däbritz, A. King, E. Gottlieb, C. Halsey, Research into cancer metabolomics: Towards a clinical metamorphosis. Semin. Cell Dev. Biol. 43, 52-64 (2015
185. J. M. Buescher, M. R. Antoniewicz, L. G. Boros, S. C. Burgess, H. Brunengraber, C. B. Clish, R. J. DeBerardinis, O. Feron, C. Frezza, B. Ghesquiere, E. Gottlieb, K. Hiller, R. G. Jones, J. J. Kamphorst, R. G. Kibbey, A. C. Kimmelman, J. W. Locasale, S. Y. Lunt, O. D. K. Maddocks, C. Malloy, C. M. Metallo, E. J. Meuillet, J. Munger, A roadmap for interpreting 13C metabolite labeling patterns from cells. Curr. Opin. Biotechnol. 34, 189-201 (2015
186. R. J. DeBerardinis, C. B. Thompson, Cellular metabolism and disease: What do metabolic outliers teach us?. Cell 148, 1132-1144 (2012
187. O. C. Andronesi, O. Rapalino, E. Gerstner, A. Chi, T. T. Batchelor, D. P. Cahill, A. G. Sorensen, B. R. Rosen, Detection of oncogenic IDH1 mutations using magnetic resonance spectroscopy of 2-hydroxyglutarate. J. Clin. Invest. 123, 3659-3663 (2013
188. C. Lussey-Lepoutre, A. Bellucci, A. Morin, A. Buffet, L. Amar, M. Janin, C. Ottolenghi, F. Zinzindohoué, G. Autret, N. Burnichon, E. Robidel, B. Banting, S. Fontaine, C.-A. Cuenod, P. Benit, P. Rustin, P. Halimi, L. Fournier, A.-P. Gimenez-Roqueplo, J. Favier, B. Tavitian, In vivo detection of succinate by magnetic resonance spectroscopy as a hallmark of SDHx mutations in paraganglioma. Clin. Cancer Res. 22, 1120-1129 (2016
189. N. M. Vacanti, A. S. Divakaruni, C. R. Green, S. J. Parker, R. R. Henry, T. P. Ciaraldi, A. N. Murphy, C. M. Metallo, Regulation of substrate utilization by the mitochondrial pyruvate carrier. Mol. Cell 56, 425-435 (2014
190. C. Yang, B. Ko, C. T. Hensley, L. Jiang, A. T. Wasti, J. Kim, J. Sudderth, M. A. Calvaruso, L. Lumata, M. Mitsche, J. Rutter, M. E. Merritt, R. J. DeBerardinis, Glutamine oxidation maintains the TCA cycle and cell survival during impaired mitochondrial pyruvate transport. Mol. Cell 56, 414-424 (2014
191. J. C. Schell, K. A. Olson, L. Jiang, A. J. Hawkins, J. G. Van Vranken, J. Xie, R. A. Egnatchik, E. G. Earl, R. J. DeBerardinis, J. Rutter, A role for the mitochondrial pyruvate carrier as a repressor of the Warburg effect and colon cancer cell growth. Mol. Cell 56, 400-413 (2014
192. I. Marin-Valencia, C. Yang, T. Mashimo, S. Cho, H. Baek, X.-L. Yang, K. N. Rajagopalan, M. Maddie, V. Vemireddy, Z. Zhao, L. Cai, L. Good, B. P. Tu, K. J. Hatanpaa, B. E. Mickey, J. M. Matés, J. M. Pascual, E. A. Maher, C. R. Malloy, R. J. DeBerardinis, Robert M. Bachoo, Analysis of tumor metabolism reveals mitochondrial glucose oxidation in genetically diverse human glioblastomas in the mouse brain in vivo. Cell Metab. 15, 827-837 (2012
193. M. O. Yuneva, T. W. M. Fan, T. D. Allen, R. M. Higashi, D. V. Ferraris, T. Tsukamoto, J. M. Matés, F. J. Alonso, C. Wang, Y. Seo, X. Chen, J. M. Bishop, The metabolic profile of tumors depends on both the responsible genetic lesion and tissue type. Cell Metab. 15, 157-170 (2012
194. E. A. Maher, I. Marin-Valencia, R. M. Bachoo, T. Mashimo, J. Raisanen, K. J. Hatanpaa, A. Jindal, F. M. Jeffrey, C. Choi, C. Madden, D. Mathews, J. M. Pascual, B. E. Mickey, C. R. Malloy, R. J. DeBerardinis, Metabolism of [U-13 C]glucose in human brain tumors in vivo. NMR Biomed. 25, 1234-1244 2012
195. K. Sellers, M. P. Fox, M. Bousamra II, S. P. Slone, R. M. Higashi, D. M. Miller, Y. Wang, J. Yan, M. O. Yuneva, R. Deshpande, A. N. Lane, T. W.-M. Fan, Pyruvate carboxylase is critical for non-small-cell lung cancer proliferation. J. Clin. Invest. 125, 687-698 (2015
196. T. W. M. Fan, A. N. Lane, R. M. Higashi, M. A. Farag, H. Gao, M. Bousamra, D. M. Miller, Altered regulation of metabolic pathways in human lung cancer discerned by 13C stable isotope-resolved metabolomics (SIRM). Mol. Cancer 8, 41 (2009
197. C. T. Hensley, B. Faubert, Q. Yuan, N. Lev-Cohain, E. Jin, J. Kim, L. Jiang, B. Ko, R. Skelton, L. Loudat, M. Wodzak, C. Klimko, E. McMillan, Y. Butt, M. Ni, D. Oliver, J. Torrealba, C. R. Malloy, K. Kernstine, R. E. Lenkinski, R. J. DeBerardinis, Metabolic heterogeneity in human lung tumors. Cell 164, 681-694 (2016
198. S. M. Davidson, T. Papagiannakopoulos, B. A. Olenchock, J. E. Heyman, M. A. Keibler, A. Luengo, M. R. Bauer, A. K. Jha, J. P. O'Brien, K. A. Pierce, D. Y. Gui, L. B. Sullivan, T. M. Wasylenko, L. Subbaraj, C. R. Chin, G. Stephanopolous, B. T. Mott, T. Jacks, C. B. Clish, M. G. Vander Heiden, Environment impacts the metabolic dependencies of ras-driven non-small cell lung cancer. Cell Metab. 23, 517-528 (2016
199. K. Birsoy, T. Wang, W. W. Chen, E. Freikman, M. Abu-Remaileh, D. M. Sabatini, An essential role of the mitochondrial electron transport chain in cell proliferation is to enable aspartate synthesis. Cell 162, 540-551 (2015
200. L. B. Sullivan, D. Y. Gui, A. M. Hosios, L. N. Bush, E. Freinkman, M. G. Vander Hediden, Supporting aspartate biosynthesis is an essential function of respiration in proliferating cells. Cell 162, 552-563 (2015