The Regulation of NRF2 by Nutrient-Responsive Signaling and Its Role in Anabolic Cancer Metabolism

Antioxidants and Redox Signaling

Volumn 29, Issue 17, 2018, Pages 1774-1791

  Lee, Sae Bom ^a   Sellers, Brianna N ^a   Denicola, Gina M ^a  

^a H LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE   (United States)

Author keywords

cysteine; glycine; KEAP1; metabolism; NRF2; serine

Indexed keywords

AMINO ACID; ASPARAGINE; CYSTEINE; GLUCOSE; GLUTAMINE; GLYCINE; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE KINASE; IRON; KELCH LIKE ECH ASSOCIATED PROTEIN 1; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHOPROTEIN PHOSPHATASE; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE; SERINE; SIRTUIN 2; TRANSCRIPTION FACTOR NRF2; TRICARBOXYLIC ACID; ANTIOXIDANT;

AMINO ACID METABOLISM; BIOSYNTHESIS; CANCER CELL; CARCINOGENESIS; CELL ENERGY; CELL METABOLISM; CELL PROLIFERATION; CITRIC ACID CYCLE; COMPETITIVE INHIBITION; COMPLEX FORMATION; ELECTRON TRANSPORT; GENE EXPRESSION; HUMAN; IRON METABOLISM; MALIGNANT NEOPLASM; NONHUMAN; NUCLEAR REPROGRAMMING; NUTRIENT; NUTRIENT AVAILABILITY; OXIDATIVE STRESS; PRIORITY JOURNAL; PROTEIN FUNCTION; PROTEIN PROCESSING; PROTEIN PROTEIN INTERACTION; PROTEIN SYNTHESIS; REVIEW; SIGNAL TRANSDUCTION; UNFOLDED PROTEIN RESPONSE; ANIMAL; METABOLISM; NEOPLASM; PATHOLOGY;

ANIMALS; ANTIOXIDANTS; CELL PROLIFERATION; HUMANS; KELCH-LIKE ECH-ASSOCIATED PROTEIN 1; NEOPLASMS; NF-E2-RELATED FACTOR 2; NUTRIENTS; SIGNAL TRANSDUCTION;

EID: 85055656350     PISSN: 15230864     EISSN: 15577716     Source Type: Journal    
DOI: 10.1089/ars.2017.7356     Document Type: Review

References (149)

1. Adam J, Hatipoglu E, O'Flaherty L, Ternette N, Sahgal N, Lockstone H, Baban D, Nye E, Stamp GW, Wolhuter K, Stevens M, Fischer R, Carmeliet P, Maxwell PH, Pugh CW, Frizzell N, Soga T, Kessler BM, El-Bahrawy M, Ratcliffe PJ, and Pollard PJ. 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
2. Agyeman AS, Chaerkady R, Shaw PG, Davidson NE, Visvanathan K, Pandey A, and Kensler TW. Transcriptomic and proteomic profiling of KEAP1 disrupted and sulforaphane-treated human breast epithelial cells reveals common expression profiles. Breast Cancer Res Treat 132: 175-187, 2012
3. Ahn CS and Metallo CM. Mitochondria as biosynthetic factories for cancer proliferation. Cancer Metab 3: 1, 2015
4. Alam J, Stewart D, Touchard C, Boinapally S, Choi AM, and Cook JL. Nrf2, a Cap'n'Collar transcription factor, regulates induction of the heme oxygenase-1 gene. J Biol Chem 274: 26071-26078, 1999
5. AlamNA, Rowan AJ,WorthamNC, Pollard PJ,MitchellM, Tyrer JP, Barclay E, Calonje E, Manek S,Adams SJ, Bowers PW, Burrows NP, Charles-Holmes R, Cook LJ, Daly BM, Ford GP, Fuller LC, Hadfield-Jones SE, Hardwick N, Highet AS, Keefe M, MacDonald-Hull SP, Potts ED, Crone M, Wilkinson S,Camacho-Martinez F, Jablonska S,Ratnavel R, MacDonald A, Mann RJ, Grice K, Guillet G, Lewis-Jones MS, McGrath H, Seukeran DC, Morrison PJ, Fleming S, Rahman S, Kelsell D, Leigh I, Olpin S, and Tomlinson IP. Genetic and functional analyses of FH mutations inmultiple cutaneous and uterine leiomyomatosis, hereditary leiomyomatosis and renal cancer, and fumarate hydratase deficiency. Hum Mol Genet 12: 1241-1252, 2003
6. Ashrafian H,Czibik G, Bellahcene M, Aksentijevic D,Smith AC, Mitchell SJ, Dodd MS, Kirwan J, Byrne JJ, Ludwig C, Isackson H, Yavari A, Stottrup NB, Contractor H, Cahill TJ, Sahgal N, Ball DR, Birkler RI, Hargreaves I, Tennant DA, Land J, Lygate CA, Johannsen M, Kharbanda RK, Neubauer S, Redwood C, Cabo R, Ahmet I, Talan M, Gunther UL, Robinson AJ, Viant MR, Pollard PJ, Tyler DJ, and Watkins H. Fumarate is cardioprotective via activation of the Nrf2 antioxidant pathway. Cell Metab 15: 361-371, 2012
7. Bae SH, Sung SH, Oh SY, Lim JM, Lee SK, Park YN, Lee HE, Kang D, and Rhee SG. Sestrins activate Nrf2 by promoting p62-dependent autophagic degradation of Keap1 and prevent oxidative liver damage. Cell Metab 17: 73-84, 2013
8. Baird L, Lleres D, Swift S, and Dinkova-Kostova AT. Regulatory flexibility in the Nrf2-mediated stress response is conferred by conformational cycling of the Keap1-Nrf2 protein complex. Proc Natl Acad Sci U S A 110: 15259-15264, 2013
9. Balasubramanian MN, Butterworth EA, and Kilberg MS. Asparagine synthetase: regulation by cell stress and involvement in tumor biology. Am J Physiol Endocrinol Metab 304: E789-E799, 2013
10. Bauer DE, Hatzivassiliou G, Zhao F, Andreadis C, and Thompson CB. ATP citrate lyase is an important component of cell growth and transformation. Oncogene 24: 6314-6322, 2005
11. Ben-Sahra I, Hoxhaj G, Ricoult SJ, Asara JM, and Manning BD. mTORC1 induces purine synthesis through control of the mitochondrial tetrahydrofolate cycle. Science 351: 728-733, 2016
12. Berkers CR, Maddocks OD, Cheung EC, Mor I, and Vousden KH. Metabolic regulation by p53 family members. Cell Metab 18: 617-633, 2013
13. Birge RB, Boeltz S, Kumar S, Carlson J, Wanderley J, Calianese D, Barcinski M, Brekken RA, Huang X, Hutchins JT, Freimark B, Empig C, Mercer J, Schroit AJ, Schett G, and HerrmannM. Phosphatidylserine is a global immunosuppressive signal in efferocytosis, infectious disease, and cancer. Cell Death Differ 23: 962-978, 2016
14. Bogdan AR, Miyazawa M, Hashimoto K, and Tsuji Y. Regulators of iron homeostasis: new players in metabolism, cell death, and disease. Trends Biochem Sci 41: 274-286, 2016
15. Breslow DK and Weissman JS. Membranes in balance: mechanisms of sphingolipid homeostasis. Mol Cell 40: 267-279, 2010
16. Brzoska K, Stepkowski TM, and Kruszewski M. Basal PIR expression in HeLa cells is driven by NRF2 via evolutionary conserved antioxidant response element. Mol Cell Biochem 389: 99-111, 2014
17. Camp ND, James RG, Dawson DW, Yan F, Davison JM, Houck SA, Tang X, Zheng N, Major MB, and Moon RT. Wilms tumor gene on X chromosome (WTX) inhibits degradation of NRF2 protein through competitive binding to KEAP1 protein. J Biol Chem 287: 6539-6550, 2012
18. Campbell MR, Karaca M, Adamski KN, Chorley BN, Wang X, and Bell DA. Novel hematopoietic target genes in the NRF2-mediated transcriptional pathway. Oxid Med Cell Longev 2013: 120305, 2013
19. Cancer Genome Atlas Research N. Comprehensive genomic characterization of squamous cell lung cancers. Nature 489: 519-525, 2012
20. Carracedo A, Cantley LC, and Pandolfi PP. Cancer metabolism: fatty acid oxidation in the limelight. Nat Rev Cancer 13: 227-232, 2013
21. Chen W, Jiang T, Wang H, Tao S, Lau A, Fang D, and Zhang DD. Does Nrf2 contribute to p53-mediated control of cell survival and death? Antioxid Redox Signal 17: 1670-1675, 2012
22. Chen W, Sun Z, Wang XJ, Jiang T, Huang Z, Fang D, and Zhang DD. Direct interaction between Nrf2 and p21(Cip1/ WAF1) upregulates the Nrf2-mediated antioxidant response. Mol Cell 34: 663-673, 2009
23. Chio, II, Jafarnejad SM, Ponz-Sarvise M, Park Y, Rivera K, Palm W, Wilson J, Sangar V, Hao Y, Ohlund D, Wright K, Filippini D, Lee EJ, Da Silva B, Schoepfer C, Wilkinson JE, Buscaglia JM, DeNicola GM, Tiriac H, Hammell M, Crawford HC, Schmidt EE, Thompson CB, Pappin DJ, Sonenberg N, and Tuveson DA. NRF2 promotes tumor maintenance by modulating mRNA translation in pancreatic cancer. Cell 166: 963-976, 2016
24. Chowdhry S, Zhang Y, McMahon M, Sutherland C, Cuadrado A, and Hayes JD. Nrf2 is controlled by two distinct beta-TrCP recognition motifs in its Neh6 domain, one of which can be modulated by GSK-3 activity. Oncogene 32: 3765-3781, 2013
25. Cullinan SB, Zhang D, Hannink M, Arvisais E, Kaufman RJ, and Diehl JA. Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival. Mol Cell Biol 23: 7198-7209, 2003
26. Nicola GM, Chen PH, Mullarky E, Sudderth JA, Hu Z, Wu D, Tang H, Xie Y, Asara JM, Huffman KE, Wistuba, II, Minna JD, DeBerardinis RJ, and Cantley LC. NRF2 regulates serine biosynthesis in non-small cell lung cancer. Nat Genet 47: 1475-1481, 2015
27. Nicola GM, Karreth FA, Humpton TJ, Gopinathan A, Wei C, Frese K, Mangal D, Yu KH, Yeo CJ, Calhoun ES, Scrimieri F, Winter JM, Hruban RH, Iacobuzio-Donahue C, Kern SE, Blair IA, and Tuveson DA. Oncogeneinduced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature 475: 106-109, 2011
28. Ding B, Parmigiani A, Divakaruni AS, Archer K, Murphy AN, and Budanov AV. Sestrin2 is induced by glucose starvation via the unfolded protein response and protects cells from non-canonical necroptotic cell death. Sci Rep 6: 22538, 2016
29. Duran A, Amanchy R, Linares JF, Joshi J, Abu-Baker S, Porollo A, Hansen M, Moscat J, and Diaz-Meco MT. p62 is a key regulator of nutrient sensing in the mTORC1 pathway. Mol Cell 44: 134-146, 2011
30. Duru N, Gernapudi R, Zhang Y, Yao Y, Lo PK, Wolfson B, and Zhou Q. NRF2/miR-140 signaling confers radioprotection to human lung fibroblasts. Cancer Lett 369: 184-191, 2015
31. Eagle H. Nutrition needs of mammalian cells in tissue culture. Science 122: 501-514, 1955
32. Fan J, Ye J, Kamphorst JJ, Shlomi T, Thompson CB, and Rabinowitz JD. Quantitative flux analysis reveals folatedependent NADPH production. Nature 510: 298-302, 2014
33. Franke TF, Kaplan DR, Cantley LC, and Toker A. Direct regulation of the Akt proto-oncogene product by phosphatidylinositol-3,4-bisphosphate. Science 275: 665-668, 1997
34. Frezza C, Zheng L, Folger O, Rajagopalan KN, MacKenzie ED, Jerby L, Micaroni M, Chaneton B, Adam J, Hedley A, Kalna G, Tomlinson IP, Pollard PJ, Watson DG, Deberardinis RJ, Shlomi T, Ruppin E, and Gottlieb E. Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase. Nature 477: 225-228, 2011
35. Gomes P, Outeiro TF, and Cavadas C. Emerging Role of Sirtuin 2 in the Regulation of Mammalian Metabolism. Trends Pharmacol Sci 36: 756-768, 2015
36. Guo JY, Karsli-Uzunbas G, Mathew R, Aisner SC, Kamphorst JJ, Strohecker AM, Chen G, Price S, Lu W, Teng X, Snyder E, Santanam U, Dipaola RS, Jacks T, Rabinowitz JD, and White E. Autophagy suppresses progression of K-ras-induced lung tumors to oncocytomas and maintains lipid homeostasis. Genes Dev 27: 1447-1461, 2013
37. Harding HP, Novoa I, Zhang Y, Zeng H, Wek R, Schapira M, and Ron D. Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell 6: 1099-1108, 2000
38. Hast BE, Cloer EW, Goldfarb D, Li H, Siesser PF, Yan F, Walter V, Zheng N, Hayes DN, and Major MB. Cancer-derived mutations in KEAP1 impair NRF2 degradation but not ubiquitination. Cancer Res 74: 808-817, 2014
39. Hast BE, Goldfarb D, Mulvaney KM, Hast MA, Siesser PF, Yan F, Hayes DN, and Major MB. Proteomic analysis of ubiquitin ligase KEAP1 reveals associated proteins that inhibit NRF2 ubiquitination. Cancer Res 73: 2199-2210, 2013
40. Hawkes HJ, Karlenius TC, and Tonissen KF. Regulation of the human thioredoxin gene promoter and its key substrates: a study of functional and putative regulatory elements. Biochim Biophys Acta 1840: 303-314, 2014
41. Hayes JD and Dinkova-Kostova AT. The Nrf2 regulatory network provides an interface between redox and intermediary metabolism. Trends Biochem Sci 39: 199-218, 2014
42. Hayes JD and McMahon M. NRF2 and KEAP1 mutations: permanent activation of an adaptive response in cancer. Trends Biochem Sci 34: 176-188, 2009
43. Hirotsu Y, Katsuoka F, Funayama R, Nagashima T, Nishida Y, Nakayama K, Engel JD, and Yamamoto M. Nrf2-MafG heterodimers contribute globally to antioxidant and metabolic networks. Nucleic Acids Res 40: 10228-10239, 2012
44. Horike N, Sakoda H, Kushiyama A, Ono H, Fujishiro M, Kamata H, Nishiyama K, Uchijima Y, Kurihara Y, Kurihara H, and Asano T. AMP-activated protein kinase activation increases phosphorylation of glycogen synthase kinase 3beta and thereby reduces cAMP-responsive element transcriptional activity and phosphoenolpyruvate carboxykinase C gene expression in the liver. J Biol Chem 283: 33902-33910, 2008
45. Hosios AM, Hecht VC, Danai LV, Johnson MO, Rathmell JC, Steinhauser ML, Manalis SR, and Vander Heiden MG. Amino acids rather than glucose account for the majority of cell mass in proliferating mammalian cells. Dev Cell 36: 540-549, 2016
46. Ichimura Y, Waguri S, Sou YS, Kageyama S, Hasegawa J, Ishimura R, Saito T, Yang Y, Kouno T, Fukutomi T, Hoshii T, Hirao A, Takagi K, Mizushima T, Motohashi H, Lee MS, Yoshimori T, Tanaka K, Yamamoto M, and Komatsu M. Phosphorylation of p62 activates the Keap1-Nrf2 pathway during selective autophagy. Mol Cell 51: 618-631, 2013
47. Inami Y, Waguri S, Sakamoto A, Kouno T, Nakada K, Hino O, Watanabe S, Ando J, Iwadate M, Yamamoto M, Lee MS, Tanaka K, and Komatsu M. Persistent activation of Nrf2 through p62 in hepatocellular carcinoma cells. J Cell Biol 193: 275-284, 2011
48. Jewell JL, Kim YC, Russell RC, Yu FX, Park HW, Plouffe SW, Tagliabracci VS, and Guan KL. Metabolism. Differential regulation of mTORC1 by leucine and glutamine. Science 347: 194-198, 2015
49. Jiang T, Harder B, Rojo Vega M, Wong PK, Chapman E, and Zhang DD. p62 links autophagy and Nrf2 signaling. Free Radic Biol Med 88: 199-204, 2015
50. Joo MS, Kim WD, Lee KY, Kim JH, Koo JH, and Kim SG. AMPK facilitates nuclear accumulation of Nrf2 by phosphorylating at serine 550. Mol Cell Biol 36: 1931-1942, 2016
51. Karapetian RN, Evstafieva AG, Abaeva IS, Chichkova NV, Filonov GS, Rubtsov YP, Sukhacheva EA, Melnikov SV, Schneider U, Wanker EE, and Vartapetian AB. Nuclear oncoprotein prothymosin alpha is a partner of Keap1: implications for expression of oxidative stressprotecting genes. Mol Cell Biol 25: 1089-1099, 2005
52. Katsuoka F, Motohashi H, Ishii T, Aburatani H, Engel JD, and Yamamoto M. Genetic evidence that small maf proteins are essential for the activation of antioxidant response element-dependent genes. Mol Cell Biol 25: 8044-8051, 2005
53. Katsuoka F, Yamazaki H, and Yamamoto M. Small Maf deficiency recapitulates the liver phenotypes of Nrf1-and Nrf2-deficient mice. Genes Cells 21: 1309-1319, 2016
54. Kaufman RJ, Scheuner D, Schroder M, Shen X, Lee K, Liu CY, and Arnold SM. The unfolded protein response in nutrient sensing and differentiation. Nat Rev Mol Cell Biol 3: 411-421, 2002
55. Kerins MJ, Vashisht A, Liang BX, Duckworth SJ, Praslicka BJ, Wohlschlegel JA, and Ooi A. Fumarate mediates a chronic proliferative signal in fumarate hydratase inactivated cancer cells by increasing transcription and translation of ferritin genes. Mol Cell Biol 37: e00079-17, 2017
56. Kinch L, Grishin NV, and Brugarolas J. Succination of Keap1 and activation of Nrf2-dependent antioxidant pathways in FH-deficient papillary renal cell carcinoma type 2. Cancer Cell 20: 418-420, 2011
57. Klippel A, Kavanaugh WM, Pot D, and Williams LT. A specific product of phosphatidylinositol 3-kinase directly activates the protein kinase Akt through its pleckstrin homology domain. Mol Cell Biol 17: 338-344, 1997
58. Kobayashi M, Kato H, Hada H, Itoh-Nakadai A, Fujiwara T, Muto A, Inoguchi Y, Ichiyanagi K, Hojo W, Tomosugi N, Sasaki H, Harigae H, and Igarashi K. Iron-heme-Bach1 axis is involved in erythroblast adaptation to iron deficiency. Haematologica 102: 454-465, 2017
59. Komatsu M, Kurokawa H, Waguri S, Taguchi K, Kobayashi A, Ichimura Y, Sou YS, Ueno I, Sakamoto A, Tong KI, Kim M, Nishito Y, Iemura S, Natsume T, Ueno T, Kominami E, Motohashi H, Tanaka K, and Yamamoto M. The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1. Nat Cell Biol 12: 213-223, 2010
60. Kulkarni SR, Donepudi AC, Xu J, Wei W, Cheng QC, Driscoll MV, Johnson DA, Johnson JA, Li X, and Slitt AL. Fasting induces nuclear factor E2-related factor 2 and ATP-binding Cassette transporters via protein kinase A and Sirtuin-1 in mouse and human. Antioxid Redox Signal 20: 15-30, 2014
61. Kunkel GT, Maceyka M, Milstien S, and Spiegel S. Targeting the sphingosine-1-phosphate axis in cancer, inflammation and beyond. Nat Rev Drug Discov 12: 688-702, 2013
62. Labuschagne CF, van den Broek NJ, Mackay GM, Vousden KH, and Maddocks OD. Serine, but not glycine, supports one-carbon metabolism and proliferation of cancer cells. Cell Rep 7: 1248-1258, 2014
63. Lau A, Wang XJ, Zhao F, Villeneuve NF, Wu T, Jiang T, Sun Z, White E, and Zhang DD. A noncanonical mechanism of Nrf2 activation by autophagy deficiency: direct interaction between Keap1 and p62. Mol Cell Biol 30: 3275-3285, 2010
64. Leventis PA and Grinstein S. The distribution and function of phosphatidylserine in cellular membranes. Annu Rev Biophys 39: 407-427, 2010
65. Levy HR, Raineri RR, and Nevaldine BH. On the structure and catalytic function of mammary glucose 6-phosphate dehydrogenase. J Biol Chem 241: 2181-2187, 1966
66. Lewerenz J, Hewett SJ, Huang Y, Lambros M, Gout PW, Kalivas PW, Massie A, Smolders I, Methner A, Pergande M, Smith SB, Ganapathy V, and Maher P. The cystine/ glutamate antiporter system x(c)(-) in health and disease: from molecular mechanisms to novel therapeutic opportunities. Antioxid Redox Signal 18: 522-555, 2013
67. Lewis CA, Parker SJ, Fiske BP, McCloskey D, Gui DY, Green CR, Vokes NI, Feist AM, Vander Heiden MG, and Metallo CM. Tracing compartmentalized NADPH metabolism in the cytosol and mitochondria of mammalian cells. Mol Cell 55: 253-263, 2014
68. Lien EC, Lyssiotis CA, Juvekar A, Hu H, Asara JM, Cantley LC, and Toker A. Glutathione biosynthesis is a metabolic vulnerability in PI(3)K/Akt-driven breast cancer. Nat Cell Biol 18: 572-578, 2016
69. Lim J, Lachenmayer ML, Wu S, Liu W, Kundu M, Wang R, Komatsu M, Oh YJ, Zhao Y, and Yue Z. Proteotoxic stress induces phosphorylation of p62/SQSTM1 by ULK1 to regulate selective autophagic clearance of protein aggregates. PLoS Genet 11: e1004987, 2015
70. Liu F, Rehmani I, Esaki S, Fu R, Chen L, de Serrano V, and Liu A. Pirin is an iron-dependent redox regulator of NFkappaB. Proc Natl Acad Sci U S A 110: 9722-9727, 2013
71. Locasale JW. Serine, glycine and one-carbon units: cancer metabolism in full circle. Nat Rev Cancer 13: 572-583, 2013
72. Locasale JW, Grassian AR, Melman T, Lyssiotis CA, Mattaini KR, Bass AJ, Heffron G, Metallo CM, Muranen T, Sharfi H, Sasaki AT, Anastasiou D, Mullarky E, Vokes NI, Sasaki M, Beroukhim R, Stephanopoulos G, Ligon AH, Meyerson M, Richardson AL, Chin L, Wagner G, Asara JM, Brugge JS, Cantley LC, and Vander Heiden MG. Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis. Nat Genet 43: 869-874, 2011
73. Lu SC. Regulation of glutathione synthesis. Mol Aspects Med 30: 42-59, 2009
74. Ludtmann MH, Angelova PR, Zhang Y, Abramov AY, and Dinkova-Kostova AT. Nrf2 affects the efficiency of mitochondrial fatty acid oxidation. Biochem J 457: 415-424, 2014
75. Lunt SY and Vander Heiden MG. Aerobic glycolysis: meeting the metabolic requirements of cell proliferation. Annu Rev Cell Dev Biol 27: 441-464, 2011
76. Ma J, Cai H, Wu T, Sobhian B, Huo Y, Alcivar A, Mehta M, Cheung KL, Ganesan S, Kong AN, Zhang DD, and Xia B. PALB2 interacts with KEAP1 to promote NRF2 nuclear accumulation and function. Mol Cell Biol 32: 1506-1517, 2012
77. Maddocks OD, Berkers CR, Mason SM, Zheng L, Blyth K, Gottlieb E, and Vousden KH. Serine starvation induces stress and p53-dependent metabolic remodelling in cancer cells. Nature 493: 542-546, 2013
78. Maddocks OD, Labuschagne CF, Adams PD, and Vousden KH. Serine metabolism supports the methionine cycle and DNA/RNA methylation through de novo ATP synthesis in cancer cells. Mol Cell 61: 210-221, 2016
79. Maehama T and Dixon JE. The tumor suppressor, PTEN/ MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem 273: 13375-13378, 1998
80. Malhotra D, Portales-Casamar E, Singh A, Srivastava S, Arenillas D, Happel C, Shyr C, Wakabayashi N, Kensler TW, Wasserman WW, and Biswal S. Global mapping of binding sites for Nrf2 identifies novel targets in cell survival response through ChIP-Seq profiling and network analysis. Nucleic Acids Res 38: 5718-5734, 2010
81. Marro S, Chiabrando D, Messana E, Stolte J, Turco E, Tolosano E, and Muckenthaler MU. Heme controls ferroportin1 (FPN1) transcription involving Bach1, Nrf2 and a MARE/ARE sequence motif at position-7007 of the FPN1 promoter. Haematologica 95: 1261-1268, 2010
82. McBean GJ. The transsulfuration pathway: a source of cysteine for glutathione in astrocytes. Amino Acids 42: 199-205, 2012
83. Mihaylova MM and Shaw RJ. The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nat Cell Biol 13: 1016-1023, 2011
84. Misra I and Griffith OW. Expression and purification of human gamma-glutamylcysteine synthetase. Protein Expr Purif 13: 268-276, 1998
85. Mitsuishi Y, Taguchi K, Kawatani Y, Shibata T, Nukiwa T, Aburatani H, Yamamoto M, and Motohashi H. Nrf2 redirects glucose and glutamine into anabolic pathways in metabolic reprogramming. Cancer Cell 22: 66-79, 2012
86. Mo C, Wang L, Zhang J, Numazawa S, Tang H, Tang X, Han X, Li J, Yang M, Wang Z, Wei D, and Xiao H. The crosstalk between Nrf2 and AMPK signal pathways is important for the anti-inflammatory effect of berberine in LPS-stimulated macrophages and endotoxin-shocked mice. Antioxid Redox Signal 20: 574-588, 2014
87. Moinova HR and Mulcahy RT. Up-regulation of the human gamma-glutamylcysteine synthetase regulatory subunit gene involves binding of Nrf-2 to an electrophile responsive element. Biochem Biophys Res Commun 261: 661-668, 1999
88. Mullen PJ, Yu R, Longo J, Archer MC, and Penn LZ. The interplay between cell signalling and the mevalonate pathway in cancer. Nat Rev Cancer 16: 718-731, 2016
89. Nairz M, Schleicher U, Schroll A, Sonnweber T, Theurl I, Ludwiczek S, Talasz H, Brandacher G, Moser PL, Muckenthaler MU, Fang FC, Bogdan C, and Weiss G. Nitric oxide-mediated regulation of ferroportin-1 controls macrophage iron homeostasis and immune function in Salmonella infection. J Exp Med 210: 855-873, 2013
90. Ni HM, Woolbright BL, Williams J, Copple B, Cui W, Luyendyk JP, Jaeschke H, and Ding WX. Nrf2 promotes the development of fibrosis and tumorigenesis in mice with defective hepatic autophagy. J Hepatol 61: 617-625, 2014
91. Nicklin P, Bergman P, Zhang B, Triantafellow E, Wang H, Nyfeler B, Yang H, Hild M, Kung C, Wilson C, Myer VE, MacKeigan JP, Porter JA, Wang YK, Cantley LC, Finan PM, and Murphy LO. Bidirectional transport of amino acids regulates mTOR and autophagy. Cell 136: 521-534, 2009
92. Ohta T, Iijima K, Miyamoto M, Nakahara I, Tanaka H, Ohtsuji M, Suzuki T, Kobayashi A, Yokota J, Sakiyama T, Shibata T, Yamamoto M, and Hirohashi S. Loss of Keap1 function activates Nrf2 and provides advantages for lung cancer cell growth. Cancer Res 68: 1303-1309, 2008
93. Ooi A, Dykema K, Ansari A, Petillo D, Snider J, Kahnoski R, Anema J, Craig D, Carpten J, Teh BT, and Furge KA. CUL3 and NRF2 mutations confer an NRF2 activation phenotype in a sporadic form of papillary renal cell carcinoma. Cancer Res 73: 2044-2051, 2013
94. Ooi A and Furge KA. Fumarate hydratase inactivation in renal tumors: HIF1alpha, NRF2, and ''cryptic targets'' of transcription factors. Chin J Cancer 31: 413-420, 2012
95. Ooi A, Wong JC, Petillo D, Roossien D, Perrier-Trudova V, Whitten D, Min BW, Tan MH, Zhang Z, Yang XJ, Zhou M, Gardie B, Molinie V, Richard S, Tan PH, Teh BT, and Furge KA. An antioxidant response phenotype shared between hereditary and sporadic type 2 papillary renal cell carcinoma. Cancer Cell 20: 511-523, 2011
96. Pankiv S, Lamark T, Bruun JA, Overvatn A, Bjorkoy G, and Johansen T. Nucleocytoplasmic shuttling of p62/ SQSTM1 and its role in recruitment of nuclear polyubiquitinated proteins to promyelocytic leukemia bodies. J Biol Chem 285: 5941-5953, 2010
97. Patra KC and Hay N. The pentose phosphate pathway and cancer. Trends Biochem Sci 39: 347-354, 2014
98. Pietsch EC, Chan JY, Torti FM, and Torti SV. Nrf2 mediates the induction of ferritin H in response to xenobiotics and cancer chemopreventive dithiolethiones. J Biol Chem 278: 2361-2369, 2003
99. Pochini L, Scalise M, Galluccio M, and Indiveri C. Membrane transporters for the special amino acid glutamine: structure/function relationships and relevance to human health. Front Chem 2: 61, 2014
100. Possemato R, Marks KM, Shaul YD, Pacold ME, Kim D, Birsoy K, Sethumadhavan S, Woo HK, Jang HG, Jha AK, Chen WW, Barrett FG, Stransky N, Tsun ZY, Cowley GS, Barretina J, Kalaany NY, Hsu PP, Ottina K, Chan AM, Yuan B, Garraway LA, Root DE, Mino-Kenudson M, Brachtel EF, Driggers EM, and Sabatini DM. Functional genomics reveal that the serine synthesis pathway is essential in breast cancer. Nature 476: 346-350, 2011
101. Pyne NJ and Pyne S. Sphingosine 1-phosphate and cancer. Nat Rev Cancer 10: 489-503, 2010
102. Rada P, Rojo AI, Chowdhry S, McMahon M, Hayes JD, and Cuadrado A. SCF/{beta}-TrCP promotes glycogen synthase kinase 3-dependent degradation of the Nrf2 transcription factor in a Keap1-independent manner. Mol Cell Biol 31: 1121-1133, 2011
103. Ro SH, Semple IA, Park H, Park H, Park HW, Kim M, Kim JS, and Lee JH. Sestrin2 promotes Unc-51-like kinase 1 mediated phosphorylation of p62/sequestosome-1. FEBS J 281: 3816-3827, 2014
104. Rohrig F and Schulze A. The multifaceted roles of fatty acid synthesis in cancer. Nat Rev Cancer 16: 732-749, 2016
105. Rojo AI, Rada P, Mendiola M, Ortega-Molina A, Wojdyla K, Rogowska-Wrzesinska A, Hardisson D, Serrano M, and Cuadrado A. The PTEN/NRF2 axis promotes human carcinogenesis. Antioxid Redox Signal 21: 2498-2514, 2014
106. Rosenfeldt MT, O'Prey J, Morton JP, Nixon C, MacKay G, Mrowinska A, Au A, Rai TS, Zheng L, Ridgway R, Adams PD, Anderson KI, Gottlieb E, Sansom OJ, and Ryan KM. p53 status determines the role of autophagy in pancreatic tumour development. Nature 504: 296-300, 2013
107. Saito T, Ichimura Y, Taguchi K, Suzuki T, Mizushima T, Takagi K, Hirose Y, Nagahashi M, Iso T, Fukutomi T, Ohishi M, Endo K, Uemura T, Nishito Y, Okuda S, Obata M, Kouno T, Imamura R, Tada Y, Obata R, Yasuda D, Takahashi K, Fujimura T, Pi J, Lee MS, Ueno T, Ohe T, Mashino T, Wakai T, Kojima H, Okabe T, Nagano T, Motohashi H, Waguri S, Soga T, Yamamoto M, Tanaka K, and Komatsu M. p62/Sqstm1 promotes malignancy of HCV-positive hepatocellular carcinoma through Nrf2-dependent metabolic reprogramming. Nat Commun 7: 12030, 2016
108. Salazar M, Rojo AI, Velasco D, de Sagarra RM, and Cuadrado A. Glycogen synthase kinase-3beta inhibits the xenobiotic and antioxidant cell response by direct phosphorylation and nuclear exclusion of the transcription factor Nrf2. J Biol Chem 281: 14841-14851, 2006
109. Sasaki H, Sato H, Kuriyama-Matsumura K, Sato K, Maebara K, Wang H, Tamba M, Itoh K, Yamamoto M, and Bannai S. Electrophile response elementmediated induction of the cystine/glutamate exchange transporter gene expression. J Biol Chem 277: 44765-44771, 2002
110. Sato H, Nomura S, Maebara K, Sato K, Tamba M, and Bannai S. Transcriptional control of cystine/glutamate transporter gene by amino acid deprivation. Biochem Biophys Res Commun 325: 109-116, 2004
111. Schroit AJ, Madsen JW, and Tanaka Y. In vivo recognition and clearance of red blood cells containing phosphatidylserine in their plasma membranes. J Biol Chem 260: 5131-5138, 1985
112. Schug ZT, Vande Voorde J, and Gottlieb E. The metabolic fate of acetate in cancer. Nat Rev Cancer 16: 708-717, 2016
113. Sengupta R and Holmgren A. Thioredoxin and glutaredoxin-mediated redox regulation of ribonucleotide reductase. World J Biol Chem 5: 68-74, 2014
114. Shibata T, Kokubu A, Saito S, Narisawa-Saito M, Sasaki H, Aoyagi K, Yoshimatsu Y, Tachimori Y, Kushima R, Kiyono T, and Yamamoto M. NRF2 mutation confers malignant potential and resistance to chemoradiation therapy in advanced esophageal squamous cancer. Neoplasia 13: 864-873, 2011
115. Singh A, Bodas M, Wakabayashi N, Bunz F, and Biswal S. Gain of Nrf2 function in non-small-cell lung cancer cells confers radioresistance. Antioxid Redox Signal 13: 1627-1637, 2010
116. Singh A, Happel C, Manna SK, Acquaah-Mensah G, Carrerero J, Kumar S, Nasipuri P, Krausz KW, Wakabayashi N, Dewi R, Boros LG, Gonzalez FJ, Gabrielson E, Wong KK, Girnun G, and Biswal S. Transcription factor NRF2 regulates miR-1 and miR-206 to drive tumorigenesis. J Clin Invest 123: 2921-2934, 2013
117. Soo PC, Horng YT, Lai MJ, Wei JR, Hsieh SC, Chang YL, Tsai YH, and Lai HC. Pirin regulates pyruvate catabolism by interacting with the pyruvate dehydrogenase E1 subunit and modulating pyruvate dehydrogenase activity. J Bacteriol 189: 109-118, 2007
118. Stipanuk MH, Dominy JE, Jr., Lee JI, and Coloso RM. Mammalian cysteine metabolism: new insights into regulation of cysteine metabolism. J Nutr 136: 1652S-1659S, 2006
119. Stone SJ and Vance JE. Phosphatidylserine synthase-1 and-2 are localized to mitochondria-associated membranes. J Biol Chem 275: 34534-34540, 2000
120. Storch KJ, Wagner DA, Burke JF, and Young VR. Quantitative study in vivo of methionine cycle in humans using [methyl-2H3]-and [1-13C]methionine. Am J Physiol 255: E322-E331, 1988
121. Sun X, Ou Z, Chen R, Niu X, Chen D, Kang R, and Tang D. Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells. Hepatology 63: 173-184, 2016
122. Sun Z, Zhang S, Chan JY, and Zhang DD. Keap1 controls postinduction repression of the Nrf2-mediated antioxidant response by escorting nuclear export of Nrf2. Mol Cell Biol 27: 6334-6349, 2007
123. Taguchi K, Hirano I, Itoh T, Tanaka M, Miyajima A, Suzuki A, Motohashi H, and Yamamoto M. Nrf2 enhances cholangiocyte expansion in Pten-deficient livers. Mol Cell Biol 34: 900-913, 2014
124. Takeda TA, Mu A, Tai TT, Kitajima S, and Taketani S. Continuous de novo biosynthesis of haem and its rapid turnover to bilirubin are necessary for cytoprotection against cell damage. Sci Rep 5: 10488, 2015
125. Theurl I, Hilgendorf I, Nairz M, Tymoszuk P, Haschka D, Asshoff M, He S, Gerhardt LM, Holderried TA, Seifert M, Sopper S, Fenn AM, Anzai A, Rattik S, McAlpine C, Theurl M, Wieghofer P, Iwamoto Y, Weber GF, Harder NK, Chousterman BG, Arvedson TL, McKee M, Wang F, Lutz OM, Rezoagli E, Babitt JL, Berra L, Prinz M, Nahrendorf M, Weiss G, Weissleder R, Lin HY, and Swirski FK. On-demand erythrocyte disposal and iron recycling requires transient macrophages in the liver. Nat Med 22: 945-951, 2016
126. Tong KI, Katoh Y, Kusunoki H, Itoh K, Tanaka T, and Yamamoto M. Keap1 recruits Neh2 through binding to ETGE and DLG motifs: characterization of the two-site molecular recognition model. Mol Cell Biol 26: 2887-2900, 2006
127. Torti SV and Torti FM. Iron and cancer: more ore to be mined. Nat Rev Cancer 13: 342-355, 2013
128. Ubuka T and Meister A. Studies on the utilization of asparagine by mouse leukemia cells. J Natl Cancer Inst 46: 291-298, 1971
129. Umemura A, He F, Taniguchi K, Nakagawa H, Yamachika S, Font-Burgada J, Zhong Z, Subramaniam S, Raghunandan S, Duran A, Linares JF, Reina-Campos M, Umemura S, Valasek MA, Seki E, Yamaguchi K, Koike K, Itoh Y, Diaz-Meco MT, Moscat J, and Karin M. p62, upregulated during preneoplasia, induces hepatocellular carcinogenesis by maintaining survival of stressed HCCinitiating cells. Cancer Cell 29: 935-948, 2016
130. Vander Heiden MG, Cantley LC, and Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324: 1029-1033, 2009
131. Velichkova M and Hasson T. Keap1 regulates the oxidationsensitive shuttling of Nrf2 into and out of the nucleus via a Crm1-dependent nuclear export mechanism. Mol Cell Biol 25: 4501-4513, 2005
132. Vivanco I and Sawyers CL. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2: 489-501, 2002
133. Wakabayashi N, Dinkova-Kostova AT, Holtzclaw WD, Kang MI, Kobayashi A, Yamamoto M, Kensler TW, and Talalay P. Protection against electrophile and oxidant stress by induction of the phase 2 response: fate of cysteines of the Keap1 sensor modified by inducers. Proc Natl Acad Sci U S A 101: 2040-2045, 2004
134. Wakabayashi N, Itoh K, Wakabayashi J, Motohashi H, Noda S, Takahashi S, Imakado S, Kotsuji T, Otsuka F, Roop DR, Harada T, Engel JD, and Yamamoto M. Keap1-null mutation leads to postnatal lethality due to constitutive Nrf2 activation. Nat Genet 35: 238-245, 2003
135. Wang Q, Bailey CG, Ng C, Tiffen J, Thoeng A, Minhas V, Lehman ML, Hendy SC, Buchanan G, Nelson CC, Rasko JE, and Holst J. Androgen receptor and nutrient signaling pathways coordinate the demand for increased amino acid transport during prostate cancer progression. Cancer Res 71: 7525-7536, 2011
136. Wang Q, Tiffen J, Bailey CG, Lehman ML, Ritchie W, Fazli L, Metierre C, Feng YJ, Li E, Gleave M, Buchanan G, Nelson CC, Rasko JE, and Holst J. Targeting amino acid transport in metastatic castration-resistant prostate cancer: effects on cell cycle, cell growth, and tumor development. J Natl Cancer Inst 105: 1463-1473, 2013
137. Wek SA, Zhu S, and Wek RC. The histidyl-tRNA synthetase-related sequence in the eIF-2 alpha protein kinase GCN2 interacts with tRNA and is required for activation in response to starvation for different amino acids. Mol Cell Biol 15: 4497-4506, 1995
138. Wu KC, Cui JY, and Klaassen CD. Beneficial role of Nrf2 in regulating NADPH generation and consumption. Toxicol Sci 123: 590-600, 2011
139. Wu T, Zhao F, Gao B, Tan C, Yagishita N, Nakajima T, Wong PK, Chapman E, Fang D, and Zhang DD. Hrd1 suppresses Nrf2-mediated cellular protection during liver cirrhosis. Genes Dev 28: 708-722, 2014
140. Yang A, Rajeshkumar NV, Wang X, Yabuuchi S, Alexander BM, Chu GC, Von Hoff DD, Maitra A, and Kimmelman AC. Autophagy is critical for pancreatic tumor growth and progression in tumors with p53 alterations. Cancer Discov 4: 905-913, 2014
141. Yang M and Vousden KH. Serine and one-carbon metabolism in cancer. Nat Rev Cancer 16: 650-662, 2016
142. Yang S, Wang X, Contino G, Liesa M, Sahin E, Ying H, Bause A, Li Y, Stommel JM, Dell'antonio G, Mautner J, Tonon G, Haigis M, Shirihai OS, Doglioni C, Bardeesy N, and Kimmelman AC. Pancreatic cancers require autophagy for tumor growth. Genes Dev 25: 717-729, 2011
143. Yang X, Park SH, Chang HC, Shapiro JS, Vassilopoulos A, Sawicki KT, Chen C, Shang M, Burridge PW, Epting CL, Wilsbacher LD, Jenkitkasemwong S, Knutson M, Gius D, and Ardehali H. Sirtuin 2 regulates cellular iron homeostasis via deacetylation of transcription factor NRF2. J Clin Invest 127, 1505, 2017
144. Ye J, Fan J, Venneti S, Wan YW, Pawel BR, Zhang J, Finley LW, Lu C, Lindsten T, Cross JR, Qing G, Liu Z, Simon MC, Rabinowitz JD, and Thompson CB. Serine catabolism regulates mitochondrial redox control during hypoxia. Cancer Discov 4: 1406-1417, 2014
145. Ye J, Kumanova M, Hart LS, Sloane K, Zhang H, De Panis DN, Bobrovnikova-Marjon E, Diehl JA, Ron D, and Koumenis C. The GCN2-ATF4 pathway is critical for tumour cell survival and proliferation in response to nutrient deprivation. EMBO J 29: 2082-2096, 2010
146. Ye P, Mimura J, Okada T, Sato H, Liu T, Maruyama A, Ohyama C, and Itoh K. Nrf2-and ATF4-dependent upregulation of xCT modulates the sensitivity of T24 bladder carcinoma cells to proteasome inhibition. Mol Cell Biol 34: 3421-3434, 2014
147. Zhang J, Fan J, Venneti S, Cross JR, Takagi T, Bhinder B, Djaballah H, Kanai M, Cheng EH, Judkins AR, Pawel B, Baggs J, Cherry S, Rabinowitz JD, and Thompson CB. Asparagine plays a critical role in regulating cellular adaptation to glutamine depletion. Mol Cell 56: 205-218, 2014
148. Zimmermann K, Baldinger J, Mayerhofer B, Atanasov AG, Dirsch VM, and Heiss EH. Activated AMPK boosts the Nrf2/HO-1 signaling axis-A role for the unfolded protein response. Free Radic Biol Med 88: 417-426, 2015
149. Zipper LM and Mulcahy RT. Erk activation is required for Nrf2 nuclear localization during pyrrolidine dithiocarbamate induction of glutamate cysteine ligase modulatory gene expression in HepG2 cells. Toxicol Sci 73: 124-134, 2003