NRF2 addiction in cancer cells

Cancer Science

Volumn 109, Issue 4, 2018, Pages 900-911

  Kitamura, Hiroshi ^a   Motohashi, Hozumi ^a  

^a TOHOKU UNIVERSITY   (Japan)

Author keywords

KEAP1; metabolic reprogramming; NRF2; therapeutic resistance; tumor microenvironment

Indexed keywords

FUMARATE HYDRATASE; KELCH LIKE ECH ASSOCIATED PROTEIN 1; SEQUESTOSOME 1; TRANSCRIPTION FACTOR NRF2; ANTINEOPLASTIC AGENT; ANTIOXIDANT;

CANCER CELL; CANCER PATIENT; CANCER PROGNOSIS; DNA METHYLATION; EXON SKIPPING; GENE ACTIVATION; HUMAN; NONHUMAN; PRIORITY JOURNAL; PROMOTER REGION; PROTEIN FUNCTION; PROTEIN PROTEIN INTERACTION; REVIEW; SOMATIC MUTATION; TRANSCRIPTION INITIATION; TUMOR MICROENVIRONMENT; ANIMAL; CARCINOGENESIS; DRUG EFFECTS; DRUG RESISTANCE; METABOLISM; NEOPLASM; OXIDATIVE STRESS;

ANIMALS; ANTINEOPLASTIC AGENTS; ANTIOXIDANTS; CARCINOGENESIS; DRUG RESISTANCE, NEOPLASM; HUMANS; NEOPLASMS; NF-E2-RELATED FACTOR 2; OXIDATIVE STRESS;

EID: 85043479323     PISSN: 13479032     EISSN: 13497006     Source Type: Journal    
DOI: 10.1111/cas.13537     Document Type: Review

References (80)

1. Motohashi H, Yamamoto M. NRF2-Keap1 defines a physiologically important stress response mechanism. Trends Mol Med. 2004;10:549-557.
2. Tong KI, Katoh Y, Kusunoki H, Itoh K, Tanaka T, Yamamoto M. Keap1 recruits Neh2 through binding to ETGE and DLG motifs: characterization of the two-site molecular recognition model. Mol Cell Biol. 2006;26:2887-2900.
3. Tong KI, Padmanabhan B, Kobayashi A, et al. Different electrostatic potentials define ETGE and DLG motifs as hinge and latch in oxidative stress response. Mol Cell Biol. 2007;27:7511-7521.
4. Ogura T, Tong KI, Mio K, et al. Keap1 is a forked-stem dimer structure with two large spheres enclosing the intervening, double glycine repeat, and C-terminal domains. Proc Natl Acad Sci USA. 2010;107:2842-2847.
5. Enomoto A, Itoh K, Nagayoshi E, et al. High sensitivity of NRF2 knockout mice to acetaminophen hepatotoxicity associated with decreased expression of ARE-regulated drug metabolizing enzymes and antioxidant genes. Toxicol Sci. 2001;59:169-177.
6. Okawa H, Motohashi H, Kobayashi A, Aburatani H, Kensler TW, Yamamoto M. Hepatocyte-specific deletion of the keap1 gene activates NRF2 and confers potent resistance against acute drug toxicity. Biochem Biophys Res Commun. 2006;339:79-88.
7. Honkura Y, Matsuo H, Murakami S, et al. NRF2 is a key target for prevention of noise-induced hearing loss by reducing oxidative damage of cochlea. Sci Rep. 2016;6:19329.
8. Kobayashi EH, Suzuki T, Funayama R, et al. NRF2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription. Nat Commun. 2016;7:11624.
9. Suzuki T, Murakami S, Biswal SS, et al. Systemic activation of NRF2 alleviates lethal autoimmune inflammation in scurfy mice. Mol Cell Biol. 2017;37:e00063-17.
10. Ramos-Gomez M, Kwak MK, Dolan PM, et al. Sensitivity to carcinogenesis is increased and chemoprotective efficacy of enzyme inducers is lost in NRF2 transcription factor-deficient mice. Proc Natl Acad Sci USA. 2001;98:3410-3415.
11. Iida K, Itoh K, Kumagai Y, et al. NRF2 is essential for the chemopreventive efficacy of oltipraz against urinary bladder carcinogenesis. Cancer Res. 2004;64:6424-6431.
12. Satoh H, Moriguchi T, Takai J, Ebina M, Yamamoto M. NRF2 prevents initiation but accelerates progression through the Kras signaling pathway during lung carcinogenesis. Cancer Res. 2013;73:4158-4168.
13. Satoh H, Moriguchi T, Saigusa D, et al. NRF2 intensifies host defense systems to prevent lung carcinogenesis, but after tumor initiation accelerates malignant cell growth. Cancer Res. 2016;76:3088-3096.
14. Satoh H, Moriguchi T, Taguchi K, et al. NRF2-deficiency creates a responsive microenvironment for metastasis to the lung. Carcinogenesis. 2010;31:1833-1843.
15. Hiramoto K, Satoh H, Suzuki T, et al. Myeloid lineage-specific deletion of antioxidant system enhances tumor metastasis. Cancer Prev Res (Phila). 2014;7:835-844.
16. Maj T, Wang W, Crespo J, et al. Oxidative stress controls regulatory T cell apoptosis and suppressor activity and PD-L1-blockade resistance in tumor. Nat Immunol. 2017;18:1332-1341.
17. Wakabayashi N, Itoh K, Wakabayashi J, et al. Keap1-null mutation leads to postnatal lethality due to constitutive NRF2 activation. Nat Genet. 2003;35:238-245.
18. Suzuki T, Seki S, Hiramoto K, et al. Hyperactivation of NRF2 in early tubular development induces nephrogenic diabetes insipidus. Nat Commun. 2017;8:14577.
19. Murakami S, Suzuki T, Harigae H, Romeo PH, Yamamoto M, Motohashi H. NRF2 activation impairs quiescence and bone marrow reconstitution capacity of hematopoietic stem cells. Mol Cell Biol. 2017;37:e00086-17.
20. Zhao M, Xu H, Zhang B, Hong B, Yan W, Zhang J. Impact of nuclear factor erythroid-derived 2–like 2 and p62/sequestosome expression on prognosis of patients with gliomas. Human Pathol. 2015;46:843-849.
21. Kanamori M, Higa T, Sonoda Y, et al. Activation of the NRF2 pathway and its impact on the prognosis of anaplastic glioma patients. Neuro Oncol. 2015;17:555-565.
22. Tsai WC, Hueng DY, Lin CR, Yang TC, Gao HQ. NRF2 expressions correlate with WHO grades in gliomas and meningiomas. Int J Mol Sci. 2016;17:E722.
23. DeNicola GM, Chen PH, Mullarky E, et al. NRF2 regulates serine biosynthesis in non-small cell lung cancer. Nat Genet. 2015;47:1475-1481.
24. Solis LM, Behrens C, Dong W, et al. NRF2 and Keap1 abnormalities in non-small cell lung carcinoma and association with clinicopathologic features. Clin Cancer Res. 2010;16:3743-3753.
25. Arbour KC, Jordan E, Kim HR, et al. Effects of co-occurring genomic alterations on outcomes in patients with KRAS-mutant non-small cell lung cancer. Clin Cancer Res. 2018;24:334-340.
26. Inoue D, Suzuki T, Mitsuishi Y, et al. Accumulation of p62/SQSTM1 is associated with poor prognosis in patients with lung adenocarcinoma. Cancer Sci. 2012;103:760-766.
27. Romero R, Sayin VI, Davidson SM, et al. Keap1 loss promotes Kras-driven lung cancer and results in dependence on glutaminolysis. Nat Med. 2017;23:1362-1368.
28. Shibata T, Ohta T, Tong KI, et al. Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy. Proc Natl Acad Sci USA. 2008;105:13568-13573.
29. Shibata T, Kokubu A, Saito S, et al. NRF2 mutation confers malignant potential and resistance to chemoradiation therapy in advanced esophageal squamous cancer. Neoplasia. 2011;13:864-873.
30. Kawasaki Y, Okumura H, Uchikado Y, et al. NRF2 is useful for predicting the effect of chemoradiation therapy on esophageal squamous cell carcinoma. Ann Surg Oncol. 2014;21:2347-2352.
31. Martinez VD, Vucic EA, Thu KL, Pikor LA, Lam S, Lam WL. Disruption of KEAP1/CUL3/RBX1 E3-ubiquitin ligase complex components by multiple genetic mechanisms: association with poor prognosis in head and neck cancer. Head Neck. 2015;37:727-734.
32. Shibata T, Saito S, Kokubu A, et al. Global downstream pathway analysis reveals a dependence of oncogenic NF-E2–related factor 2 mutation on the mtor growth signaling pathway. Cancer Res. 2010;70:9095-9105.
33. Onodera Y, Motohashi H, Takagi K, et al. NRF2 immunolocalization in human breast cancer patients as a prognostic factor. Endocr Relat Cancer. 2014;21:241-252.
34. Zhang M, Zhang C, Zhang L, et al. NRF2 is a potential prognostic marker and promotes proliferation and invasion in human hepatocellular carcinoma. BMC Cancer. 2015;15:531.
35. Chen J, Yu Y, Ji T, et al. Clinical implication of Keap1 and phosphorylated NRF2 expression in hepatocellular carcinoma. Cancer Med. 2016;5:2678-2687.
36. Hayden A, Douglas J, Sommerlad M, et al. The NRF2 transcription factor contributes to resistance to cisplatin in bladder cancer. Urol Oncol. 2014;32:806-814.
37. Isohookana J, Haapasaari KM, Soini Y, Karihtala P. Keap1 expression has independent prognostic value in pancreatic adenocarcinomas. Diagn Pathol. 2015;10:28.
38. Soini Y, Eskelinen M, Juvonen P, et al. Nuclear NRF2 expression is related to a poor survival in pancreatic adenocarcinoma. Pathol Res Pract. 2014;210:35-39.
39. Ma JQ, Tuersun H, Jiao SJ, Zheng JH, Xiao JB, Hasim A. Functional role of NRF2 in cervical carcinogenesis. PLoS ONE. 2015;10:e0133876.
40. Hintsala HR, Jokinen E, Haapasaari KM, et al. NRF2/Keap1 pathway and expression of oxidative stress lesions 8-hydroxy-2’-deoxyguanosine and nitrotyrosine in melanoma. Anticancer Res. 2016;36:1497-1506.
41. Konstantinopoulos PA, Spentzos D, Fountzilas E, et al. Keap1 mutations and NRF2 pathway activation in epithelial ovarian cancer. Cancer Res. 2011;71:5081-5089.
42. Liew PL, Hsu CS, Liu WM, Lee YC, Lee YC, Chen CL. Prognostic and predictive values of NRF2, Keap1, p16 and E-cadherin expression in ovarian epithelial carcinoma. Int J Clin Exp Pathol. 2015;8:5642-5649.
43. Kawasaki Y, Ishigami S, Arigami T, et al. Clinicopathological significance of nuclear factor (erythroid-2)-related factor 2 (NRF2) expression in gastric cancer. BMC Cancer. 2015;15:5.
44. Hu XF, Yao J, Gao SG, et al. NRF2 overexpression predicts prognosis and 5-FU resistance in gastric cancer. Asian Pac J Cancer Prev. 2013;13:5231-5235.
45. Ji L, Wei Y, Jiang T, Wang S. Correlation of NRF2, NQO1, MRP1, cmyc and p53 in colorectal cancer and their relationships to clinicopathologic features and survival. Int J Clin Exp Pathol. 2014;7:1124-1131.
46. Kandoth C, McLellan MD, Vandin F, et al. Mutational landscape and significance across 12 major cancer types. Nature. 2013;502:333-339.
47. Padmanabhan B, Tong KI, Ohta T, et al. Structural basis for defects of Keap1 activity provoked by its point mutations in lung cancer. Mol Cell. 2006;21:689-700.
48. Fukutomi T, Takagi K, Mizushima T, Ohuchi N, Yamamoto M. Kinetic, thermodynamic, and structural characterizations of the association between NRF2-DLGex degron and Keap1. Mol Cell Biol. 2014;34:832-846.
49. Goldstein LD, Lee J, Gnad F, et al. Recurrent loss of NFE2L2 exon 2 is a mechanism for NRF2 pathway activation in human cancers. Cell Rep. 2016;16:2605-2617.
50. Fabrizio FP, Costantini M, Copetti M, et al. Keap1/NRF2 pathway in kidney cancer: frequent methylation of KEAP1 gene promoter in clear renal cell carcinoma. Oncotarget. 2017;8:11187-11198.
51. Ichimura Y, Waguri S, Sou YS, et al. Phosphorylation of p62 activates the Keap1-NRF2 pathway during selective autophagy. Mol Cell. 2013;51:618-631.
52. Komatsu M, Kurokawa H, Waguri S, et al. The selective autophagy substrate p62 activates the stress responsive transcription factor NRF2 through inactivation of Keap1. Nat Cell Biol. 2010;12:213-223.
53. Inami Y, Waguri S, Sakamoto A, et al. Persistent activation of NRF2 through p62 in hepatocellular carcinoma cells. J Cell Biol. 2011;193:275-284.
54. Adam J, Hatipoglu E, O'Flaherty L, et al. 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. 2011;20:524-537.
55. Ooi A, Wong JC, Petillo D, et al. An antioxidant response phenotype shared between hereditary and sporadic type 2 papillary renal cell carcinoma. Cancer Cell. 2011;20:511-523.
56. Suzuki T, Shibata T, Takaya T, et al. Regulatory nexus of synthesis and degradation deciphers cellular NRF2 expression levels. Mol Cell Biol. 2013;33:2402-2412.
57. DeNicola GM, Karreth FA, Humpton TJ, et al. Oncogene-induced NRF2 transcription promotes ROS detoxification and tumorigenesis. Nature. 2011;475:106-109.
58. Ji X, Chen SH, Zhu L, et al. Knockdown of NF-E2-related factor 2 inhibits the proliferation and growth of U251MG human glioma cells in a mouse xenograft model. Oncol Rep. 2013;30:157-164.
59. Fan Z, Wirth AK, Chen D, et al. NRF2-Keap1 pathway promotes cell proliferation and diminishes ferroptosis. Oncogenesis. 2017;6:e371.
60. Zhu J, Wang H, Sun Q, et al. NRF2 is required to maintain the self-renewal of glioma stem cells. BMC Cancer. 2013;13:380.
61. Tsuchida K, Tsujita T, Hayashi M, et al. Halofuginone enhances the chemo-sensitivity of cancer cells by suppressing NRF2 accumulation. Free Radic Biol Med. 2017;103:236-247.
62. Tao S, Wang S, Moghaddam SJ, et al. Oncogenic KRAS confers chemoresistance by upregulating NRF2. Cancer Res. 2014;74:7430-7441.
63. Mitsuishi Y, Taguchi K, Kawatani Y, et al. NRF2 redirects glucose and glutamine into anabolic pathways in metabolic reprogramming. Cancer Cell. 2012;22:66-79.
64. Krall EB, Wang B, Munoz DM, et al. KEAP1 loss modulates sensitivity to kinase targeted therapy in lung cancer. eLife 2017;6:e18970.
65. Jeong Y, Hoang NT, Lovejoy A, et al. Role of KEAP1/NRF2 and TP53 mutations in lung squamous cell carcinoma development and radiation resistance. Cancer Discov. 2017;7:86-101.
66. Oshimori N, Oristian D, Fuchs E. TGF-β promotes heterogeneity and drug resistance in squamous cell carcinoma. Cell. 2015;160:963-976.
67. Lien EC, Lyssiotis CA, Juvekar A, et al. Glutathione biosynthesis is a metabolic vulnerability in PI(3)K/Akt-driven breast cancer. Nat Cell Biol. 2016;18:572-578.
68. Chen L, Brewer MD, Guo L, et al. Enhanced degradation of misfolded proteins promotes tumorigenesis. Cell Rep. 2017;18:3142-3154.
69. Todoric J, Antonucci L, Di Caro G, et al. Stress-activated NRF2-MDM2 cascade controls neoplastic progression in pancreas. Cancer Cell. 2017;32:824-839.e8
70. Chio IIC, Jafarnejad SM, Ponz-Sarvise M, et al. NRF2 promotes tumor maintenance by modulating mRNA translation in pancreatic cancer. Cell. 2016;166:963-976.
71. Rocha CR, Kajitani GS, Quinet A, Fortunato RS, Menck CF. NRF2 and glutathione are key resistance mediators to temozolomide in glioma and melanoma cells. Oncotarget. 2016;7:48081-48092.
72. Zhang P, Singh A, Yegnasubramanian S, et al. Loss of Kelch-like ECH-associated protein 1 function in prostate cancer cells causes chemoresistance and radioresistance and promotes tumor growth. Mol Cancer Ther. 2010;9:336-346.
73. Ge W, Zhao K, Wang X, et al. iASPP is an antioxidative factor and drives cancer growth and drug resistance by competing with NRF2 for Keap1 binding. Cancer Cell. 2017;32:561-573.
74. Kitamura H, Onodera Y, Murakami S, Suzuki T, Motohashi H. IL-11 contribution to tumorigenesis in an NRF2 addiction cancer model. Oncogene. 2017;36:6315-6324.
75. Taguchi K, Hirano I, Itoh T, et al. NRF2 enhances cholangiocyte expansion in Pten-deficient livers. Mol Cell Biol. 2014;34:900-913.
76. Shirasaki K, Taguchi K, Unno M, Motohashi H, Yamamoto M. NF-E2-related factor 2 promotes compensatory liver hypertrophy after portal vein branch ligation in mice. Hepatology. 2014;59:2371-2382.
77. Rada P, Rojo AI, Chowdhry S, McMahon M, Hayes JD, 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. 2011;31:1121-1133.
78. Chowdhry S, Zhang Y, McMahon M, Sutherland C, Cuadrado A, Hayes JD. NRF2 is controlled by two distinct β-TrCP recognition motifs in its Neh6 domain, one of which can be modulated by GSK-3 activity. Oncogene. 2013;32:3765-3781.
79. Taguchi K, Maher JM, Suzuki T, Kawatani Y, Motohashi H, Yamamoto M. Genetic analysis of cytoprotective functions supported by graded expression of Keap1. Mol Cell Biol. 2010;30:3016-3026.
80. Hamada S, Shimosegawa T, Taguchi K, Nabeshima T, Yamamoto M, Masamune A. Simultaneous K-ras activation and Keap1 deletion cause atrophy of pancreatic parenchyma. Am J Physiol Gastrointest Liver Physiol. 2018;314:G65-G74. ajpgi.00228.2017.