Abstract

The transcription factor Nrf2 controls the expression of genes encoding cytoprotective enzymes and proteins. Its activation is related to conformational changes in the inhibitory protein Keap1 and/or Nrf2 phosphorylation by upstream kinases. Activation of Nrf2 can lead to the induction of phase II enzymes responsible for the inactivation of potential carcinogens. This may constitute an important strategy of chemoprevention. Moreover, these enzymatic systems participating in the biotransformation of drugs can reduce their therapeutic effects, contributing to drug resistance. For this reason, a clear understanding of the role of Nrf2 is essential to assess the beneficial and adverse effects of its up-regulation, particularly in relation to the prevention and treatment of cancer. This article summarizes the current state of knowledge on the significance of Nrf2 in tumorigenesis.

References

• 1. Adams J., Kelso R., Cooley L.: The Kelch repeat superfamily of proteins:propellers of cell function. Trends Cell Biol., 2000; 10: 17-24
  Google Scholar
• 2. Akhdar H., Loyer P., Rauch C., Corlu A., Guillouzo A., Morel F.: Involvementof Nrf2 activation in resistance to 5-fluorouracil in human coloncancer HT-29 cells. Eur. J. Cancer, 2009; 45: 2219-2227
  Google Scholar
• 3. Apopa P.L., He X., Ma Q.: Phosphorylation of Nrf2 in the transcriptionactivation domain by casein kinase 2 (CK2) is critical forthe nuclear translocation and transcription activation functionof Nrf2 in IMR-32 neuroblastoma cells. J. Biochem. Mol. Toxicol.,2008; 22: 63-76
  Google Scholar
• 4. Biswas M., Chan J.Y.: Role of Nrf1 in antioxidant response elementmediatedgene expression and beyond. Toxicol. Appl. Pharmacol., 2010;244: 16-20
  Google Scholar
• 5. Bryan H.K., Olayanju A., Goldring C.E., Park B.K.: The Nrf2 cell defencepathway: Keap1-dependent and -independent mechanisms of regulation.Biochem. Pharmacol., 2013; 85: 705-717
  Google Scholar
• 6. Chan J.Y., Han X.L., Kan Y.W.: Isolation of cDNA encoding the humanNF-E2 protein. Proc. Natl. Acad. Sci. USA, 1993; 90: 11366-11370
  Google Scholar
• 7. Chan J.Y., Kwong M., Lu R., Chang J., Wang B., Yen T.S., Kan Y.W.:Targeted disruption of the ubiquitous CNC-bZIP transcription factor, Nrf-1, results in anemia and embryonic lethality in mice. EMBO J., 1998;17: 1779-1787
  Google Scholar
• 8. Chan K., Lu R., Chang J.C., Kan Y.W.: NRF2, a member of the NFE2family of transcription factors, is not essential for murine erythropoiesis,growth, and development. Proc. Natl. Acad. Sci. USA, 1996; 93:13943-13948
  Google Scholar
• 9. Cullinan S.B., Diehl J.A.: PERK-dependent activation of Nrf2 contributesto redox homeostasis and cell survival following endoplasmicreticulum stress. J. Biol. Chem., 2004; 279: 20108-20117
  Google Scholar
• 10. Cullinan S.B., Zhang D., Hannink M., Arvisais E., Kaufman R.J., DiehlJ.A.: Nrf2 is a direct PERK substrate and effector of PERK-dependent cellsurvival. Mol. Cell. Biol., 2003; 23: 7198-7209
  Google Scholar
• 11. DeNicola G.M., Karreth F.A., Humpton T.J., Gopinathan A., Wei C.,Frese K., Mangal D, Yu K.H., Yeo C.J., Calhoun E.S., Scrimieri F., WinterJ.M., Hruban R.H., Iacobuzio-Donahue C., Kern S.E., Blair I.A., TuvesonD.A.: Oncogene-induced Nrf2 transcription promotes ROS detoxificationand tumorigenesis. Nature, 2011; 475: 106-109
  Google Scholar
• 12. Dhakshinamoorthy S., Jain A.K., Bloom D.A., Jaiswal A.K.: Bach1competes with Nrf2 leading to negative regulation of the antioxidantresponse element (ARE)-mediated NAD(P)H:quinone oxidoreductase 1 gene expression and induction in response to antioxidants. J. Biol.Chem., 2005; 280: 16891-16900
  Google Scholar
• 13. Dinkova-Kostova A.T., Massiah M.A., Bozak R.E., Hicks R.J.,Talalay P.: Potency of Michael reaction acceptors as inducers ofenzymes that protect against carcinogenesis depends on their reactivitywith sulfhydryl groups. Proc. Natl. Acad. Sci. USA, 2001;98: 3404-3409
  Google Scholar
• 14. Gao A.M., Ke Z.P., Wang J.N., Yang J.Y., Chen S.Y., Chen H.: Apigeninsensitizes doxorubicin-resistant hepatocellular carcinoma BEL-7402/ADM cells to doxorubicin via inhibiting PI3K/Akt/Nrf2 pathway. Carcinogenesis,2013; 34: 1806-1814
  Google Scholar
• 15. Giudice A., Montella M.: Activation of the Nrf2-ARE signaling pathway:a promising strategy in cancer prevention. Bioessays, 2006; 28:169-181
  Google Scholar
• 16. Hanahan D., Weinberg R.A.: Hallmarks of cancer: the next generation.Cell, 2011; 144: 646-674
  Google Scholar
• 17. Hayashi A., Suzuki H., Itoh K., Yamamoto M., Sugiyama Y.: Transcriptionfactor Nrf2 is required for the constitutive and inducible expressionof multidrug resistance-associated protein 1 in mouse embryo fibroblasts.Biochem. Biophys. Res. Commun., 2003; 310: 824-829
  Google Scholar
• 18. Hayes J.D., McMahon M.: NRF2 and KEAP1 mutations: permanentactivation of an adaptive response in cancer. Trends Biochem. Sci.,2009; 34: 176-188
  Google Scholar
• 19. Holtzclaw W.D., Dinkova-Kostova A.T., Talalay P.: Protection againstelectrophile and oxidative stress by induction of phase 2 genes: thequest for the elusive sensor that responds to inducers. Adv. EnzymeRegul., 2004; 44: 335-367
  Google Scholar
• 20. Huang H.C., Nguyen T., Pickett C.B.: Phosphorylation of Nrf2 at Ser- 40 by protein kinase C regulates antioxidant response element-mediatedtranscription. J. Biol. Chem., 2002; 277: 42769-42774
  Google Scholar
• 21. Hybertson B.M., Gao B., Bose S.K., McCord J.M.: Oxidative stress inhealth and disease: the therapeutic potential of Nrf2 activation. Mol.Aspects Med., 2011; 32: 234-246
  Google Scholar
• 22. Iida K., Itoh K., Kumagai Y., Oyasu R., Hattori K., Kawai K., ShimazuiT., Akaza H., Yamamoto M.: Nrf2 is essential for the chemopreventiveefficacy of oltipraz against urinary bladder carcinogenesis. Cancer Res.,2004; 64: 6424-6431
  Google Scholar
• 23. Itoh K., Chiba T., Takahashi S., Ishii T., Igarashi K., Katoh Y., OyakeT., Hayashi N., Satoh K., Hatayama I., Yamamoto M., Nabeshima Y.: AnNrf2/small Maf heterodimer mediates the induction of phase II detoxifyingenzyme genes through antioxidant response elements. Biochem.Biophys. Res. Commun., 1997; 236: 313-322
  Google Scholar
• 24. Itoh K., Igarashi K., Hayashi N., Nishizawa M., Yamamoto M.: Cloningand characterization of a novel erythroid cell-derived CNC familytranscription factor heterodimerizing with the small Maf family proteins.Mol. Cell. Biol., 1995; 15: 4184-4193
  Google Scholar
• 25. Itoh K., Wakabayashi N., Katoh Y., Ishii T., Igarashi K., Engel J.D.,Yamamoto M.: Keap1 represses nuclear activation of antioxidant responsiveelements by Nrf2 through binding to the amino-terminalNeh2 domain. Genes Dev., 1999; 13: 76-86
  Google Scholar
• 26. Jain A.K., Bloom D.A., Jaiswal A.K.: Nuclear import and export signalsin control of Nrf2. J. Biol. Chem., 2005; 280: 29158-29168
  Google Scholar
• 27. Jain A.K., Jaiswal A.K.: GSK-3β acts upstream of Fyn kinase in regulationof nuclear export and degradation of NF-E2 related factor 2. J.Biol. Chem., 2007; 282: 16502-16510
  Google Scholar
• 28. Jain A.K., Jaiswal A.K.: Phosphorylation of tyrosine 568 controlsnuclear export of Nrf2. J. Biol. Chem., 2006; 281: 12132-12142
  Google Scholar
• 29. Jain A.K., Mahajan S., Jaiswal A.K.: Phosphorylation and dephosphorylationof tyrosine 141 regulate stability and degradation of INrf2:a novel mechanism in Nrf2 activation. J. Biol. Chem., 2008; 283: 17712-17720
  Google Scholar
• 30. Jaiswal A.K.: Nrf2 signaling in coordinated activation of antioxidantgene expression. Free Radic. Biol. Med., 2004; 36: 1199-1207
  Google Scholar
• 31. Johnson J.R., Wiliams G., Pazdur R.: End points and United StatesFood and Drug Administration approval of oncology drugs. J. Clin. Oncol.,2003; 21: 1404-1411
  Google Scholar
• 32. Kang K.W., Lee S.J., Park J.W., Kim S.G.: Phosphatidylinositol 3-kinaseregulates nuclear translocation of NF-E2-related factor 2 throughactin rearrangement in response to oxidative stress. Mol. Pharmacol.,2002; 62: 1001-1010
  Google Scholar
• 33. Katoh Y., Iida K., Kang M.I., Kobayashi A., Mizukami M., Tong K.I.,McMahon M., Hayes J.D., Itoh K, Yamamoto M.: Evolutionary conservedN-terminal domain of Nrf2 is essential for the Keap1-mediateddegradation of the protein by proteasome. Arch. Biochem. Biophys.,2005; 433: 342-350
  Google Scholar
• 34. Katoh Y., Itoh K., Yoshida E., Miyagishi M., Fukamizu A., YamamotoM.: Two domains of Nrf2 cooperatively bind CBP, a CREB bindingprotein, and synergistically activate transcription. Genes Cells,2001; 6: 857-868
  Google Scholar
• 35. Keum Y.S., Owuor E.D., Kim B.R., Hu R., Kong A.N.: Involvement ofNrf2 and JNK1 in the activation of antioxidant responsive element (ARE)by chemopreventive agent phenethyl isothiocyanate (PEITC). Pharm.Res., 2003; 20: 1351-1356
  Google Scholar
• 36. Keum Y.S., Yu S., Chang P.P., Yuan X., Kim J.H., Xu C., Han J., AgarwalA., Kong A.N.: Mechanism of action of sulforaphane: inhibition of p38mitogen-activated protein kinase isoforms contributing to the inductionof antioxidant response element-mediated heme oxygenase-1 inhuman hepatoma HepG2 cells. Cancer Res., 2006; 66: 8804-8813
  Google Scholar
• 37. Khan H., Cino E.A., Brickenden A., Fan J., Yang D., Choy W.Y.: Fuzzycomplex formation between the intrinsically disordered prothymosinα and the Kelch domain of Keap1 involved in the oxidative stress response.J. Mol. Biol., 2013; 425: 1011-1027
  Google Scholar
• 38. Khor T.O., Huang M.T., Kwon K.H., Chan J.Y., Reddy B.S., Kong A.N.:Nrf2-deficient mice have an increased susceptibility to dextran sulfatesodium-induced colitis. Cancer Res., 2006; 66: 11580-11584
  Google Scholar
• 39. Kim Y.R., Oh J.E., Kim M.S., Kang M.R., Park S.W., Han J.Y., Eom H.S.,Yoo N.J., Lee S.H.: Oncogenic NRF2 mutations in squamous cell carcinomasof oesophagus and skin. J. Pathol., 2010; 220: 446-451
  Google Scholar
• 40. Kobayashi A., Kang M.I., Watai Y., Tong K.I., Shibata T., Uchida K., YamamotoM.: Oxidative and electrophilic stresses activate Nrf2 throughinhibition of ubiquitination activity of Keap1. Mol. Cell. Biol., 2006;26: 221-229
  Google Scholar
• 41. Kobayashi M., Itoh K., Suzuki T., Osanai H., Nishikawa K., KatohY., Takagi Y., Yamamoto M.: Identification of the interactive interface and phylogenic conservation of the Nrf2-Keap1 system. Genes Cells,2002; 7: 807-820
  Google Scholar
• 42. Krajka-Kuźniak V.: Induction of phase II enzymes as a strategy in thechemoprevention of cancer and other degenerative diseases. PostępyHig. Med. Dośw., 2007; 61: 627-638
  Google Scholar
• 43. Krajka-Kuźniak V., Paluszczak J., Baer-Dubowska W.: Xanthohumolinduces phase II enzymes via Nrf2 in human hepatocytes in vitro. Toxicol.In Vitro, 2013; 27: 149-156
  Google Scholar
• 44. Kundu J.K., Surh Y.J.: Nrf2-Keap1 signaling as a potential target forchemoprevention of inflammation-associated carcinogenesis. Pharm.Res., 2010; 27: 999-1013
  Google Scholar
• 45. Lage H.: An overview of cancer multidrug resistance: a still unsolvedproblem. Cell. Mol. Life Sci., 2008; 65: 3145-3167
  Google Scholar
• 46. Lee J.H., Khor T.O., Shu L., Su Z.Y., Fuentes F., Kong A.N.: Dietaryphytochemicals and cancer prevention: Nrf2 signaling, epigenetics, andcell death mechanisms in blocking cancer initiation and progression.Pharmacol Ther., 2013; 137: 153-171
  Google Scholar
• 47. Lee J.S., Surh Y.J.: Nrf2 as a novel molecular target for chemoprevention.Cancer Lett., 2005; 224: 171-184
  Google Scholar
• 48. Lee O.H., Jain A.K., Papusha V., Jaiswal A.K.: An auto-regulatory loopbetween stress sensors INrf2 and Nrf2 controls their cellular abundance.J. Biol. Chem., 2007; 282: 36412-36420
  Google Scholar
• 49. Li W., Yu S.W., Kong A.N.: Nrf2 possesses a redox-sensitive nuclearexporting signal in the Neh5 transactivation domain. J. Biol. Chem.,2006; 281: 27251-27263
  Google Scholar
• 50. Li Y., Kong D., Wang Z., Sarkar F.H.: Regulation of microRNAs bynatural agents: an emerging field in chemoprevention and chemotherapyresearch. Pharm. Res., 2010; 27: 1027-1041
  Google Scholar
• 51. Li Y., Tollefsbol T.O.: Impact on DNA methylation in cancer preventionand therapy by bioactive dietary components. Curr. Med. Chem.,2010; 17: 2141-2151
  Google Scholar
• 52. Lin W., Shen G., Yuan X., Jain M.R., Yu S., Zhang A., Chen J.D., KongA.N.: Regulation of Nrf2 transactivation domain activity by p160 RAC3/SRC3 and other nuclear co-regulators. J. Biochem. Mol. Biol., 2006; 39:304-310
  Google Scholar
• 53. Lister A., Nedjadi T., Kitteringham N.R., Campbell F., Costello E.,Lloyd B., Copple I.M., Williams S., Owen A., Neoptolemos J.P., GoldringC.E., Park B.K.: Nrf2 is overexpressed in pancreatic cancer: implicationsfor cell proliferation and therapy. Mol. Cancer, 2011; 10: 37
  Google Scholar
• 54. Lo R., Matthews J.: The aryl hydrocarbon receptor and estrogen receptoralpha differentially modulate nuclear factor erythroid-2-relatedfactor 2 transactivation in MCF-7 breast cancer cells. Toxicol. Appl.Pharmacol., 2013; 270: 139-148
  Google Scholar
• 55. Lo S.C., Li X., Henzl M.T., Beamer L.J., Hannink M.: Structure of theKeap1:Nrf2 interface provides mechanistic insight into Nrf2 signaling.EMBO J., 2006; 25: 3605-3617
  Google Scholar
• 56. Magesh S., Chen Y., Hu L.: Small molecule modulators of Keap1-Nrf2-ARE pathway as potential preventive and therapeutic agents. Med.Res. Rev., 2012; 32: 687-726
  Google Scholar
• 57. Manson M.M., Gescher A., Hudson E.A., Plummer S.M., Squires M.S.,Prigent S.A.: Blocking and suppressing mechanisms of chemopreventionby dietary constituents. Toxicol. Lett., 2000; 112-113: 499-505
  Google Scholar
• 58. Maruyama A., Nishikawa K., Kawatani Y., Mimura J., Hosoya T., HaradaN., Yamamato M., Itoh K.: The novel Nrf2-interacting factor KAP1regulates susceptibility to oxidative stress by promoting the Nrf2-mediatedcytoprotective response. Biochem. J., 2011; 436: 387-397
  Google Scholar
• 59. McMahon M., Itoh K., Yamamoto M., Chanas S.A., Henderson C.J.,McLellan L.I., Wolf C.R., Cavin C., Hayes J.D.: The Cap’n’Collar basic leucinezipper transcription factor Nrf2 (NF-E2 p45-related factor 2) controlsboth constitutive and inducible expression of intestinal detoxificationand glutathione biosynthetic enzymes. Cancer Res., 2001; 61:3299-3307
  Google Scholar
• 60. McMahon M., Thomas N., Itoh K., Yamamoto M., Hayes J.D.: Redoxregulatedturnover of Nrf2 is determined by at least two separate proteindomains, the redox-sensitive Neh2 degron and the redox-insensitiveNeh6 degron. J. Biol. Chem., 2004; 279: 31556-31567
  Google Scholar
• 61. Mitsuishi Y., Taguchi K., Kawatani Y., Shibata T., Nukiwa T., AburataniH., Yamamoto M., Motohashi H.: Nrf2 redirects glucose and glutamineinto anabolic pathways in metabolic reprogramming. CancerCell, 2012; 22: 66-79
  Google Scholar
• 62. Moi P., Chan K., Asunis I., Cao A., Kan Y.W.: Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptionalactivator that binds to the tandem NF-E2/AP1 repeat of thebeta-globin locus control region. Proc. Natl. Acad. Sci. USA, 1994;91: 9926-9930
  Google Scholar
• 63. Motohashi H., O’Connor T., Katsuoka F., Engel J.D., Yamamoto M.:Integration and diversity of the regulatory network composed of Mafand CNC families of transcription factors. Gene, 2002; 294: 1-12
  Google Scholar
• 64. Naidu S., Vijayan V., Santoso S., Kietzmann T., Immenschuh S.: Inhibitionand genetic deficiency of p38 MAPK up-regulates heme oxygenase-1gene expression via Nrf2. J. Immunol., 2009; 182: 7048-7057
  Google Scholar
• 65. Nguyen T., Sherratt P.J., Nioi P., Yang C.S., Pickett C.B.: Nrf2 controlsconstitutive and inducible expression of ARE-driven genes througha dynamic pathway involving nucleocytoplasmic shuttling by Keap1.J. Biol. Chem., 2005; 280: 32485-32492
  Google Scholar
• 66. Nioi P., Nguyen T., Sherratt P.J., Pickett C.B.: The carboxy-terminalNeh3 domain of Nrf2 is required for transcriptional activation. Mol.Cell. Biol., 2005; 25: 10895-10906
  Google Scholar
• 67. Niture S.K., Jaiswal A.K.: Hsp90 interaction with INrf2(Keap1) mediatesstress-induced Nrf2 activation. J. Biol. Chem., 2010; 285: 36865-36875
  Google Scholar
• 68. Niture S.K., Jaiswal A.K.: Nrf2-induced antiapoptotic Bcl-xL proteinenhances cell survival and drug resistance. Free Radic. Biol. Med.,2013; 57: 119-131
  Google Scholar
• 69. Niture S.K., Jaiswal A.K.: Prothymosin-α mediates nuclear importof the INrf2/Cul3 Rbx1 complex to degrade nuclear Nrf2. J. Biol. Chem.,2009; 284: 13856-13868
  Google Scholar
• 70. Prochaska H.J., De Long M.J., Talalay P.: On the mechanisms of inductionof cancer-protective enzymes: a unifying proposal. Proc. Natl.Acad. Sci. USA, 1985; 82: 8232-8236
  Google Scholar
• 71. Rachakonda G., Xiong Y., Sekhar K.R., Stamer S.L., Liebler D.C., FreemanM.L.: Covalent modification at Cys151 dissociates the electrophilesensor Keap1 from the ubiquitin ligase CUL3. Chem. Res. Toxicol., 2008;21: 705-710
  Google Scholar
• 72. Rushmore T.H., Morton M.R., Pickett C.B.: The antioxidant responsiveelement. Activation by oxidative stress and identification of theDNA consensus sequence required for functional activity. J. Biol. Chem.,1991; 266: 11632-11639
  Google Scholar
• 73. Salazar M., Rojo A.I., Velasco D., de Sagarra R.M., Cuadrado A.: Glycogensynthase kinase-3β inhibits the xenobiotic and antioxidant cellresponse by direct phosphorylation and nuclear exclusion of the transcriptionfactor Nrf2. J. Biol. Chem., 2006; 281: 14841-14851
  Google Scholar
• 74. Saw C.L., Kong A.N.: Nuclear factor-erythroid 2-related factor 2as a chemopreventive target in colorectal cancer. Expert Opin. Ther.Targets, 2011; 15: 281-295
  Google Scholar
• 75. Singh A., Wu H., Zhang P., Happel C., Ma J., Biswal S.: Expressionof ABCG2 (BCRP) is regulated by Nrf2 in cancer cells that confers sidepopulation and chemoresistance phenotype. Mol. Cancer Ther., 2010;9: 2365-2376
  Google Scholar
• 76. Slocum S.L, Kensler T.W.: Nrf2: control of sensitivity to carcinogens.Arch. Toxicol., 2011; 85: 273-284
  Google Scholar
• 77. Sporn M.B., Liby K.T., Yore M.M., Fu L., Lopchuk J.M., Gribble G.W.:New synthetic triterpenoids: potent agents for prevention and treatmentof tissue injury caused by inflammatory and oxidative stress. J.Nat. Prod., 2011; 74: 537-545
  Google Scholar

Full text