Skip to main content
SpringerLink
Log in

The Keap1–Nrf2 pathway: promising therapeutic target to counteract ROS-mediated damage in cancers and neurodegenerative diseases

  • Review
  • Published:
Biophysical Reviews Aims and scope Submit manuscript

Abstract

The overproduction of reactive oxygen species (ROS) generates oxidative stress in cells. Oxidative stress results in various pathophysiological conditions, especially cancers and neurodegenerative diseases (NDD). The Keap1–Nrf2 [Kelch-like ECH-associated protein 1–nuclear factor (erythroid-derived 2)-like 2] regulatory pathway plays a central role in protecting cells against oxidative and xenobiotic stresses. The Nrf2 transcription factor activates the transcription of several cytoprotective genes that have been implicated in protection from cancer and NDD. The Keap1–Nrf2 system acts as a double-edged sword: Nrf2 activity protects cells and makes the cell resistant to oxidative and electrophilic stresses, whereas elevated Nrf2 activity helps in cancer cell survival and proliferation. Several groups in the recent past, from both academics and industry, have reported the potential role of Nrf2-mediated transcription to protect from cancer and NDD, resulting from mechanisms involving xenobiotic and oxidative stress. It suggests that the Keap1–Nrf2 system is a potential therapeutic target to combat cancer and NDD by designing and developing modulators (inhibitors/activators) for Nrf2 activation. Herein, we review and discuss the recent advancement in the regulation of the Keap1–Nrf2 system, its role under physiological and pathophysiological conditions including cancer and NDD, and modulators design strategies for Nrf2 activation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Abbreviations

ARE:

Antioxidant response element

AD:

Alzheimer’s disease

Aβ:

Amyloid-β

AGEs:

Advanced glycation end products

ATF4:

Activating transcription factor 4

BRG1:

Brahma-related gene 1

BTB:

Broad-complex, tramtrack and bric-à-brac

CBP:

CREB-binding protein

CDDO:

1-[2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]

CDDO-Me:

2-Cyano-3,12-dioxoolean-1,9-dien-28-oic acid methyl ester or bardoxolone methyl

CHD:

Chromodomain helicase DNA binding protein 6

CNC:

Cap ‘n’ collar

CREB:

cAMP response element binding protein

CRL:

Cullin-RING ubiquitin ligases

DJ1:

Protein deglycase DJ-1

DMF:

Dimethyl fumarate

EFA:

Electrophilic fatty acids

FAE:

Fumaric acid esters

FCCP:

Carbonyl cyanide-4-(trifluoromethoxy)phenylhydrazone

GCL:

Gamma-glutamylcysteine ligase

GCLM:

Glutamate cysteine ligase modifier

GGT:

Gamma-glutamyl transferase

GCV:

Ganciclovir

G6PD:

Glucose-6-phosphate dehydrogenase

GSH:

Glutathione

GST:

Glutathione S-transferase

HO-1:

Heme oxygenase-1

6-HAD:

6-Hydroxyldopamine

HD:

Huntington’s disease

ICH:

Intracerebral haemorrhage

IDH1:

Isocitrate dehydrogenase 1

IKKB:

Inhibitor of nuclear factor kappa-B kinase subunit beta

IR:

Ischaemia–reperfusion

IVR:

Intervening region

Keap1:

Kelch-like ECH-associated protein 1

Maf:

Musculoaponeurotic fibrosarcoma

ME1:

Malic enzyme 1

MMF:

Monomethyl fumarate

MTHFD2:

Methylenetetrahydrofolate dehydrogenase 2

NADPH:

Nicotinamide adenine dinucleotide phosphate

NDD:

Neurodegenerative diseases

NEDD8:

Neural precursor cell expressed, developmentally downregulated 8

Neh:

Nrf2–ECH homology

NFT:

Neurofibrillary tangles

NQO1:

NAD(P)H:quinone oxidoreductase 1

Nrf2:

Nuclear factor (erythroid-derived 2)-like 2

PD:

Parkinson’s disease

PGD:

Phosphogluconate dehydrogenase

PHF:

Paired helical filaments

PI3K:

Phosphoinositide 3-kinase

PPAT:

Phosphoribosyl pyrophosphate amidotransferase

QSAR:

Quantitative structure–activity relationship

RBX1:

Ring box protein 1

ROS:

Reactive oxygen species

SAH:

Subarachnoid haemorrhage

SK-II:

Sphingosine kinase inhibitor 2

SN:

Substantia nigra

SNP:

Single nucleotide polymorphism

SOD:

Superoxide dismutase

TALDO1:

Transaldolase 1

TK:

Thymidine kinase

TKT:

Transketolase

References

  • Adam J, Hatipoglu E, O’Flaherty L, Ternette N, Sahgal N, Lockstone H, Baban D, Nye E, Stamp GW, Wolhuter K, Stevens M (2011) 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(4):524–537

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Adibhatla RM, Hatcher JF (2010) Lipid oxidation and peroxidation in CNS health and disease: from molecular mechanisms to therapeutic opportunities. Antioxid Redox Signal 12(1):125–169

    Article  CAS  PubMed  Google Scholar 

  • Albin RL, Reiner A, Anderson KD, Dure LS, Handelin B, Balfour R, Whetsell WO, Penney JB, Young AB (1992) Preferential loss of striato-external pallidal projection neurons in presymptomatic Huntington’s disease. Ann Neurol 31(4):425–430

    Article  CAS  PubMed  Google Scholar 

  • Albrecht P, Bouchachia I, Goebels N, Henke N, Hofstetter HH, Issberner A, Kovacs Z, Lewerenz J, Lisak D, Maher P, Mausberg AK (2012) Effects of dimethyl fumarate on neuroprotection and immunomodulation. J Neuroinflammation 9(163):2094–2099

    Google Scholar 

  • Ariga H, Takahashi-Niki K, Kato I, Maita H, Niki T, Iguchi-Ariga SM (2013) Neuroprotective function of DJ-1 in Parkinson’s disease. Oxidative Med Cell Longev. doi:10.1155/2013/683920

    Google Scholar 

  • Aronowski J, Zhao X (2011) Molecular pathophysiology of cerebral hemorrhage: secondary brain injury. Stroke 42(6):1781–1786

    Article  PubMed  PubMed Central  Google Scholar 

  • Arrasate M, Mitra S, Schweitzer ES, Segal MR, Finkbeiner S (2004) Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death. Nature 431(7010):805–810

    Article  CAS  PubMed  Google Scholar 

  • Bae SH, Sung SH, Oh SY, Lim JM, Lee SK, Park YN, Lee HE, Kang D, Rhee SG (2013) Sestrins activate Nrf2 by promoting p62-dependent autophagic degradation of Keap1 and prevent oxidative liver damage. Cell Metab 17(1):73–84

    Article  CAS  PubMed  Google Scholar 

  • Behl C (2005) Oxidative stress in Alzheimer’s disease: implications for prevention and therapy. Springer, New York, pp 65–78

    Google Scholar 

  • Bouillez A, Rajabi H, Pitroda S, Jin C, Alam M, Kharbanda A, Tagde A, Wong KK, Kufe D (2016) Inhibition of MUC1-C suppresses MYC expression and attenuates malignant growth in KRAS mutant lung adenocarcinomas. Cancer Res 76(6):1538–1548

    Article  CAS  PubMed  Google Scholar 

  • Browne SE, Beal MF (2006) Oxidative damage in Huntington’s disease pathogenesis. Antioxid Redox Signal 8(11–12):2061–2073

    Article  CAS  PubMed  Google Scholar 

  • Bryan HK, Olayanju A, Goldring CE, Park BK (2013) The Nrf2 cell defence pathway: Keap1-dependent and -independent mechanisms of regulation. Biochem Pharmacol 85(6):705–717

    Article  CAS  PubMed  Google Scholar 

  • Calkins MJ, Jakel RJ, Johnson DA, Chan K, Kan YW, Johnson JA (2005) Protection from mitochondrial complex II inhibition in vitro and in vivo by Nrf2-mediated transcription. Proc Natl Acad Sci U S A 102(1):244–249

    Article  CAS  PubMed  Google Scholar 

  • Camp ND, James RG, Dawson DW, Yan F, Davison JM, Houck SA, Tang X, Zheng N, Major MB, Moon RT (2012) Wilms tumor gene on X chromosome (WTX) inhibits degradation of Nrf2 protein through competitive binding to Keap1 protein. J Biol Chem 287(9):6539–6550

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Canning P, Cooper CD, Krojer T, Murray JW, Pike AC, Chaikuad A, Keates T, Thangaratnarajah C, Hojzan V, Marsden BD, Gileadi O (2013) Structural basis for Cul3 protein assembly with the BTB-Kelch family of E3 ubiquitin ligases. J Biol Chem 288(11):7803–7814

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chan JY, Han XL, Kan YW (1993) Cloning of Nrf1, an NF-E2-related transcription factor, by genetic selection in yeast. Proc Natl Acad Sci U S A 90(23):11371–11375

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chan JY, Cheung MC, Moi P, Chan K, Kan YW (1995) Chromosomal localization of the human NF-E2 family of bZIP transcription factors by fluorescence in situ hybridization. Hum Genet 95(3):265–269

    Article  CAS  PubMed  Google Scholar 

  • Chauhan N, Chaunsali L, Deshmukh P, Padmanabhan B (2013) Analysis of dimerization of BTB-IVR domains of Keap1 and its interaction with Cul3, by molecular modeling. Bioinformation 9(9):450

    Article  PubMed  PubMed Central  Google Scholar 

  • Chen G, Fang Q, Zhang J, Zhou D, Wang Z (2011) Role of the Nrf2–ARE pathway in early brain injury after experimental subarachnoid hemorrhage. J Neurosci Res 89(4):515–523

    Article  CAS  PubMed  Google Scholar 

  • Cheng IC, Chen YJ, Ku CW, Huang YW, Yang CN (2015) Structural and dynamic characterization of mutated Keap1 for varied affinity toward Nrf2: a molecular dynamics simulation study. J Chem Inf Model 55(10):2178–2186

    Article  CAS  PubMed  Google Scholar 

  • Cho H, Hartsock MJ, Xu Z, He M, Duh EJ (2015) Monomethyl fumarate promotes Nrf2-dependent neuroprotection in retinal ischemia–reperfusion. J Neuroinflammation 12(1):239

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Cleasby A, Yon J, Day PJ, Richardson C, Tickle IJ, Williams PA, Callahan JF, Carr R, Concha N, Kerns JK, Qi H (2014) Structure of the BTB domain of Keap1 and its interaction with the triterpenoid antagonist CDDO. PLoS One 9(6):e98896

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Clements CM, McNally RS, Conti BJ, Mak TW, Ting JPY (2006) DJ-1, a cancer- and Parkinson’s disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2. Proc Natl Acad Sci U S A 103(41):15091–15096

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cummings JL (2004) Dementia with Lewy bodies: molecular pathogenesis and implications for classification. J Geriatr Psychiatry Neurol 17:112–119

    Article  PubMed  Google Scholar 

  • Dang J, Brandenburg LO, Rosen C, Fragoulis A, Kipp M, Pufe T, Beyer C, Wruck CJ (2012) Nrf2 expression by neurons, astroglia, and microglia in the cerebral cortical penumbra of ischemic rats. J Mol Neurosci 46(3):578–584

    Article  CAS  PubMed  Google Scholar 

  • de Zeeuw D, Akizawa T, Audhya P, Bakris GL, Chin M, Christ-Schmidt H, Goldsberry A, Houser M, Krauth M, Lambers Heerspink HJ, McMurray JJ; BECON Trial Investigators (2013) Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease. N Engl J Med 369:2492–2503

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • DeNicola GM, Karreth FA, Humpton TJ, Gopinathan A, Wei C, Frese K, Mangal D, Kenneth HY, Yeo CJ, Calhoun ES, Scrimieri F (2011) Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature 475(7354):106–109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Derjuga A, Gourley TS, Holm TM, Heng HH, Shivdasani RA, Ahmed R, Andrews NC, Blank V (2004) Complexity of CNC transcription factors as revealed by gene targeting of the Nrf3 locus. Mol Cell Biol 24(8):3286–3294

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dong T, Liu W, Shen Z, Li L, Chen S, Lei X (2016) Pterisolic acid B is a Nrf2 activator by targeting C171 within Keap1–BTB domain. Sci Rep 6:19231

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Edwards MR, Johnson B, Mire CE, Xu W, Shabman RS, Speller LN, Leung DW, Geisbert TW, Amarasinghe GK, Basler CF (2014) The Marburg virus VP24 protein interacts with Keap1 to activate the cytoprotective antioxidant response pathway. Cell Rep 6(6):1017–1025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Eftekharzadeh B, Maghsoudi N, Khodagholi F (2010) Stabilization of transcription factor Nrf2 by tBHQ prevents oxidative stress-induced amyloid beta formation in NT2N neurons. Biochimie 92(3):245–253

    Article  CAS  PubMed  Google Scholar 

  • Fahey JW, Haristoy X, Dolan PM, Kensler TW, Scholtus I, Stephenson KK, Talalay P, Lozniewski A (2002) Sulforaphane inhibits extracellular, intracellular, and antibiotic-resistant strains of Helicobacter pylori and prevents benzo[a]pyrene-induced stomach tumors. Proc Natl Acad Sci U S A 99(11):7610–7615

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Faraonio R, Vergara P, Di Marzo D, Pierantoni MG, Napolitano M, Russo T, Cimino F (2006) p53 suppresses the Nrf2-dependent transcription of antioxidant response genes. J Biol Chem 281(52):39776–39784

    Article  CAS  PubMed  Google Scholar 

  • Feigin VL, Rinkel GJ, Lawes CM, Algra A, Bennett DA, van Gijn J, Anderson CS (2005) Risk factors for subarachnoid hemorrhage: an updated systematic review of epidemiological studies. Stroke 36(12):2773–2780

    Article  PubMed  Google Scholar 

  • Filippin LI, Vercelino R, Marroni NP, Xavier RM (2008) Redox signalling and the inflammatory response in rheumatoid arthritis. Clin Exp Immunol 152(3):415–422

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Flamm ES, Demopoulos HB, Seligman ML, Poser RG, Ransohoff JO (1978) Free radicals in cerebral ischemia. Stroke 9(5):445–447

    Article  CAS  PubMed  Google Scholar 

  • Furfaro AL, Macay JRZ, Marengo B, Nitti M, Parodi A, Fenoglio D, Marinari UM, Pronzato MA, Domenicotti C, Traverso N (2012) Resistance of neuroblastoma GI-ME-N cell line to glutathione depletion involves Nrf2 and heme oxygenase-1. Free Radic Biol Med 52(2):488–496

    Article  CAS  PubMed  Google Scholar 

  • Furukawa M, Xiong Y (2005) BTB protein Keap1 targets antioxidant transcription factor Nrf2 for ubiquitination by the Cullin 3-Roc1 ligase. Mol Cell Biol 25(1):162–171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hancock R, Schaap M, Pfister H, Wells G (2013) Peptide inhibitors of the Keap1–Nrf2 protein–protein interaction with improved binding and cellular activity. Org Biomol Chem 11(21):3553–3557

    Article  CAS  PubMed  Google Scholar 

  • Hasegawa M, Takahashi H, Rajabi H, Alam M, Suzuki Y, Yin L, Tagde A, Maeda T, Hiraki M, Sukhatme VP, Kufe D (2016) Functional interactions of the cystine/glutamate antiporter, CD44v and MUC1-C oncoprotein in triple-negative breast cancer cells. Oncotarget 7(11):11756–11769

    PubMed  PubMed Central  Google Scholar 

  • Hu L, Magesh S, Chen L, Wang L, Lewis TA, Chen Y, Khodier C, Inoyama D, Beamer LJ, Emge TJ, Shen J (2013) Discovery of a small-molecule inhibitor and cellular probe of Keap1–Nrf2 protein–protein interaction. Bioorg Med Chem Lett 23(10):3039–3043

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Itoh K, Wakabayashi N, Katoh Y, Ishii T, Igarashi K, Engel JD, Yamamoto M (1999) Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev 13(1):76–86

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jakel RJ, Kern JT, Johnson DA, Johnson JA (2005) Induction of the protective antioxidant response element pathway by 6-hydroxydopamine in vivo and in vitro. Toxicol Sci 87(1):176–186

    Article  CAS  PubMed  Google Scholar 

  • Jaramillo MC, Zhang DD (2013) The emerging role of the Nrf2–Keap1 signaling pathway in cancer. Genes Dev 27(20):2179–2191

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jiang Z, Duong TQ (2016) Methylene blue treatment in experimental ischemic stroke: a mini review. Brain Circ 2(1):48–53

    Article  PubMed  PubMed Central  Google Scholar 

  • Jiang ZY, Chu HX, Xi MY, Yang TT, Jia JM, Huang JJ, Guo XK, Zhang XJ, You QD, Sun HP (2013) Insight into the intermolecular recognition mechanism between Keap1 and IKKβ combining homology modelling, protein–protein docking, molecular dynamics simulations and virtual alanine mutation. PLoS One 8(9):e75076

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jiang ZY, Xu LL, Lu MC, Chen ZY, Yuan ZW, Xu XL, Guo XK, Zhang XJ, Sun HP, You QD (2015) Structure–activity and structure–property relationship and exploratory in vivo evaluation of the nanomolar Keap1–Nrf2 protein–protein interaction inhibitor. J Med Chem 58(16):6410–6421

    Article  CAS  PubMed  Google Scholar 

  • Jiang S, Deng C, Lv J, Fan C, Hu W, Di S, Yan X, Ma Z, Liang Z, Yang Y (2016) Nrf2 weaves an elaborate network of neuroprotection against stroke. Mol Neurobiol 1–16

  • Kansanen E, Kuosmanen SM, Leinonen H, Levonen AL (2013) The Keap1–Nrf2 pathway: mechanisms of activation and dysregulation in cancer. Redox Biol 1(1):45–49

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kensler TW, Wakabayashi N (2010) Nrf2: friend or foe for chemoprevention? Carcinogenesis 31(1):90–99

    Article  CAS  PubMed  Google Scholar 

  • Khor TO, Fuentes F, Shu L, Paredes-Gonzalez X, Yang AY, Liu Y, Smiraglia DJ, Yegnasubramanian S, Nelson WG, Kong ANT (2014) Epigenetic DNA methylation of antioxidative stress regulator Nrf2 in human prostate cancer. Cancer Prev Res 7(12):1186–1197

    Article  CAS  Google Scholar 

  • Kim JE, You DJ, Lee C, Ahn C, Seong JY, Hwang JI (2010a) Suppression of NF-κB signaling by KEAP1 regulation of IKKβ activity through autophagic degradation and inhibition of phosphorylation. Cell Signal 22(11):1645–1654

    Article  CAS  PubMed  Google Scholar 

  • Kim YR, Oh JE, Kim MS, Kang MR, Park SW, Han JY, Eom HS, Yoo NJ, Lee SH (2010b) Oncogenic NRF2 mutations in squamous cell carcinomas of oesophagus and skin. J Pathol 220(4):446–451

    Article  CAS  PubMed  Google Scholar 

  • Kobayashi A, Kang MI, Okawa H, Ohtsuji M, Zenke Y, Chiba T, Igarashi K, Yamamoto M (2004) Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2. Mol Cell Biol 24(16):7130–7139

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Komatsu M, Kurokawa H, Waguri S, Taguchi K, Kobayashi A, Ichimura Y, Sou YS, Ueno I, Sakamoto A, Tong KI, Kim M (2010) The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1. Nat Cell Biol 12(3):213–223

    CAS  PubMed  Google Scholar 

  • Kontos HA (1989) Oxygen radicals in CNS damage. Chem Biol Interact 72(3):229–255

    Article  CAS  PubMed  Google Scholar 

  • Kraft AD, Johnson DA, Johnson JA (2004) Nuclear factor E2-related factor 2-dependent antioxidant response element activation by tert-butylhydroquinone and sulforaphane occurring preferentially in astrocytes conditions neurons against oxidative insult. J Neurosci 24(5):1101–1112

    Article  CAS  PubMed  Google Scholar 

  • Lau A, Villeneuve NF, Sun Z, Wong PK, Zhang DD (2008) Dual roles of Nrf2 in cancer. Pharmacol Res 58(5):262–270

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lau A, Wang XJ, Zhao F, Villeneuve NF, Wu T, Jiang T, Sun Z, White E, Zhang DD (2010) A noncanonical mechanism of Nrf2 activation by autophagy deficiency: direct interaction between Keap1 and p62. Mol Cell Biol 30(13):3275–3285

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee Y, Shin DH, Kim JH, Hong S, Choi D, Kim YJ, Kwak MK, Jung Y (2010) Caffeic acid phenethyl ester-mediated Nrf2 activation and IκB kinase inhibition are involved in NFκB inhibitory effect: structural analysis for NFκB inhibition. Eur J Pharmacol 643(1):21–28

    Article  CAS  PubMed  Google Scholar 

  • Leinonen HM, Ruotsalainen AK, Määttä AM, Laitinen HM, Kuosmanen SM, Kansanen E, Pikkarainen JT, Lappalainen JP, Samaranayake H, Lesch HP, Kaikkonen MU (2012) Oxidative stress-regulated lentiviral TK/GCV gene therapy for lung cancer treatment. Cancer Res 72(23):6227–6235

    Article  CAS  PubMed  Google Scholar 

  • Leirós M, Alonso E, Sanchez JA, Rateb ME, Ebel R, Houssen WE, Jaspars M, Alfonso A, Botana LM (2013) Mitigation of ROS insults by streptomyces secondary metabolites in primary cortical neurons. ACS Chem Neurosci 5(1):71–80

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Levy S, Forman HJ (2010) C‐Myc is a Nrf2‐interacting protein that negatively regulates phase II genes through their electrophile responsive elements. IUBMB Life 62(3):237–246

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li W, Zheng S, Higgins M, Morra RP Jr, Mendis AT, Chien CW, Ojima I, Mierke DF, Dinkova-Kostova AT, Honda T (2015) New monocyclic, bicyclic, and tricyclic ethynylcyanodienones as activators of the Keap1/Nrf2/ARE pathway and inhibitors of inducible nitric oxide synthase. J Med Chem 58(11):4738–4748

    Article  CAS  PubMed  Google Scholar 

  • Linker RA, Lee DH, Ryan S, van Dam AM, Conrad R, Bista P, Zeng W, Hronowsky X, Buko A, Chollate S, Ellrichmann G (2011) Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway. Brain 134(3):678–692

    Article  PubMed  Google Scholar 

  • Magesh S, Chen Y, Hu L (2012) Small molecule modulators of Keap1–Nrf2–ARE pathway as potential preventive and therapeutic agents. Med Res Rev 32(4):687–726

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Marcotte D, Zeng W, Hus JC, McKenzie A, Hession C, Jin P, Bergeron C, Lugovskoy A, Enyedy I, Cuervo H, Wang D (2013) Small molecules inhibit the interaction of Nrf2 and the Keap1 Kelch domain through a non-covalent mechanism. Bioorg Med Chem 21(14):4011–4019

    Article  CAS  PubMed  Google Scholar 

  • Marcus DL, Thomas C, Rodriguez C, Simberkoff K, Tsai JS, Strafaci JA, Freedman ML (1998) Increased peroxidation and reduced antioxidant enzyme activity in Alzheimer’s disease. Exp Neurol 150(1):40–44

    Article  CAS  PubMed  Google Scholar 

  • Marzec JM, Christie JD, Reddy SP, Jedlicka AE, Vuong H, Lanken PN, Aplenc R, Yamamoto T, Yamamoto M, Cho HY, Kleeberger SR (2007) Functional polymorphisms in the transcription factor Nrf2 in humans increase the risk of acute lung injury. FASEB J 21(9):2237–2246

    Article  CAS  PubMed  Google Scholar 

  • McMahon M, Thomas N, Itoh K, Yamamoto M, Hayes JD (2004) Redox-regulated turnover of Nrf2 is determined by at least two separate protein domains, the redox-sensitive Neh2 degron and the redox-insensitive Neh6 degron. J Biol Chem 279(30):31556–31567

    Article  CAS  PubMed  Google Scholar 

  • Mercado N, Kizawa Y, Ueda K, Xiong Y, Kimura G, Moses A, Curtis JM, Ito K, Barnes PJ (2014) Activation of transcription factor Nrf2 signalling by the sphingosine kinase inhibitor SKI-II is mediated by the formation of Keap1 dimers. PLoS One 9(2):e88168

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Mitsuishi Y, Taguchi K, Kawatani Y, Shibata T, Nukiwa T, Aburatani H, Yamamoto M, Motohashi H (2012) Nrf2 redirects glucose and glutamine into anabolic pathways in metabolic reprogramming. Cancer Cell 22(1):66–79

    Article  CAS  PubMed  Google Scholar 

  • Moi P, Chan K, Asunis I, Cao A, Kan YW (1994) Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the beta-globin locus control region. Proc Natl Acad Sci U S A 91(21):9926–9930

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Morito N, Yoh K, Itoh K, Hirayama A, Koyama A, Yamamoto M, Takahashi S (2003) Nrf2 regulates the sensitivity of death receptor signals by affecting intracellular glutathione levels. Oncogene 22(58):9275–9281

    Article  CAS  PubMed  Google Scholar 

  • Mosley RL, Benner EJ, Kadiu I, Thomas M, Boska MD, Hasan K, Laurie C, Gendelman HE (2006) Neuroinflammation, oxidative stress, and the pathogenesis of Parkinson’s disease. Clin Neurosci Res 6(5):261–281

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Motohashi H, O’Connor T, Katsuoka F, Engel JD, Yamamoto M (2002) Integration and diversity of the regulatory network composed of Maf and CNC families of transcription factors. Gene 294(1):1–12

    Article  CAS  PubMed  Google Scholar 

  • Muscarella LA, Parrella P, D’Alessandro V, la Torre A, Barbano R, Fontana A, Tancredi A, Guarnieri V, Balsamo T, Coco M, Copetti M (2011) Frequent epigenetics inactivation of KEAP1 gene in non-small cell lung cancer. Epigenetics 6(6):710–719

    Article  CAS  PubMed  Google Scholar 

  • Nioi P, Nguyen T, Sherratt PJ, Pickett CB (2005) The carboxy-terminal Neh3 domain of Nrf2 is required for transcriptional activation. Mol Cell Biol 25(24):10895–10906

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Niture SK, Jaiswal AK (2010) Hsp90 interaction with INrf2 (Keap1) mediates stress-induced Nrf2 activation. J Biol Chem 285(47):36865–36875

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ohnuma T, Nakayama S, Anan E, Nishiyama T, Ogura K, Hiratsuka A (2010) Activation of the Nrf2/ARE pathway via S-alkylation of cysteine 151 in the chemopreventive agent-sensor Keap1 protein by falcarindiol, a conjugated diacetylene compound. Toxicol Appl Pharmacol 244(1):27–36

    Article  CAS  PubMed  Google Scholar 

  • Ooi A, Dykema K, Ansari A, Petillo D, Snider J, Kahnoski R, Anema J, Craig D, Carpten J, Teh BT, Furge KA (2013) CUL3 and Nrf2 mutations confer an Nrf2 activation phenotype in a sporadic form of papillary renal cell carcinoma. Cancer Res 73(7):2044–2051

    Article  CAS  PubMed  Google Scholar 

  • Osburn WO, Karim B, Dolan PM, Liu G, Yamamoto M, Huso DL, Kensler TW (2007) Increased colonic inflammatory injury and formation of aberrant crypt foci in Nrf2-deficient mice upon dextran sulfate treatment. Int J Cancer 121(9):1883–1891

    Article  CAS  PubMed  Google Scholar 

  • Padmanabhan B, Tong KI, Ohta T, Nakamura Y, Scharlock M, Ohtsuji M, Kang MI, Kobayashi A, Yokoyama S, Yamamoto M (2006) Structural basis for defects of Keap1 activity provoked by its point mutations in lung cancer. Mol Cell 21(5):689–700

    Article  CAS  PubMed  Google Scholar 

  • Padmanabhan B, Nakamura Y, Yokoyama S (2008) Structural analysis of the complex of Keap1 with a prothymosin α peptide. Acta Crystallogr Sect F: Struct Biol Cryst Commun 64(4):233–238

    Article  CAS  Google Scholar 

  • Pang C, Zheng Z, Shi L, Sheng Y, Wei H, Wang Z, Ji L (2016) Caffeic acid prevents acetaminophen-induced liver injury by activating the Keap1–Nrf2 antioxidative defense system. Free Radic Biol Med 91:236–246

    Article  CAS  PubMed  Google Scholar 

  • Park JS, Kang DH, Bae SH (2015) PF-4708671, a specific inhibitor of p70 ribosomal S6 kinase 1, activates Nrf2 by promoting p62-dependent autophagic degradation of Keap1. Biochem Biophys Res Commun 466(3):499–504

    Article  CAS  PubMed  Google Scholar 

  • Qin S, Deng F, Wu W, Jiang L, Yamashiro T, Yano S, Hou DX (2014) Baicalein modulates Nrf2/Keap1 system in both Keap1-dependent and Keap1-independent mechanisms. Arch Biochem Biophys 559:53–61

    Article  CAS  PubMed  Google Scholar 

  • Rajabi H, Tagde A, Alam M, Bouillez A, Pitroda S, Suzuki Y, Kufe D (2016) DNA methylation by DNMT1 and DNMT3b methyltransferases is driven by the MUC1-C oncoprotein in human carcinoma cells. Oncogene. doi:10.1038/onc.2016.180

    PubMed Central  Google Scholar 

  • Ramos-Gomez M, Kwak MK, Dolan PM, Itoh K, Yamamoto M, Talalay P, Kensler TW (2001) Sensitivity to carcinogenesis is increased and chemoprotective efficacy of enzyme inducers is lost in Nrf2 transcription factor-deficient mice. Proc Natl Acad Sci U S A 98(6):3410–3415

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ramsey CP, Glass CA, Montgomery MB, Lindl KA, Ritson GP, Chia LA, Hamilton RL, Chu CT, Jordan-Sciutto KL (2007) Expression of Nrf2 in neurodegenerative diseases. J Neuropathol Exp Neurol 66(1):75–85

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ren J, Fan C, Chen N, Huang J, Yang Q (2011) Resveratrol pretreatment attenuates cerebral ischemic injury by upregulating expression of transcription factor Nrf2 and HO-1 in rats. Neurochem Res 36(12):2352–2362

    Article  CAS  PubMed  Google Scholar 

  • Riedl AG, Watts PM, Brown CT, Jenner P (1999) P450 and heme oxygenase enzymes in the basal ganglia and their roles in Parkinson’s disease. Adv Neurol 80:271–286

    CAS  PubMed  Google Scholar 

  • Saha A, Deshaies RJ (2008) Multimodal activation of the ubiquitin ligase SCF by Nedd8 conjugation. Mol Cell 32(1):21–31

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Saifee NH, Zheng N (2008) A ubiquitin-like protein unleashes ubiquitin ligases. Cell 135(2):209–211

    Article  CAS  PubMed  Google Scholar 

  • Schipper HM, Bennett DA, Liberman A, Bienias JL, Schneider JA, Kelly J, Arvanitakis Z (2006) Glial heme oxygenase-1 expression in Alzheimer disease and mild cognitive impairment. Neurobiol Aging 27(2):252–261

    Article  CAS  PubMed  Google Scholar 

  • Sekhar KR, Yan XX, Freeman ML (2002) Nrf2 degradation by the ubiquitin proteasome pathway is inhibited by KIAA0132, the human homolog to INrf2. Oncogene 21(44):6829–6834

    Article  CAS  PubMed  Google Scholar 

  • Shibata T, Kokubu A, Gotoh M, Ojima H, Ohta T, Yamamoto M, Hirohashi S (2008a) Genetic alteration of Keap1 confers constitutive Nrf2 activation and resistance to chemotherapy in gallbladder cancer. Gastroenterology 135(4):1358–1368

    Article  CAS  PubMed  Google Scholar 

  • Shibata T, Ohta T, Tong KI, Kokubu A, Odogawa R, Tsuta K, Asamura H, Yamamoto M, Hirohashi S (2008b) Cancer related mutations in NRF2 impair its recognition by Keap1–Cul3 E3 ligase and promote malignancy. Proc Natl Acad Sci U S A 105(36):13568–13573

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shibata T, Kokubu A, Saito S, Narisawa-Saito M, Sasaki H, Aoyagi K, Yoshimatsu Y, Tachimori Y, Kushima R, Kiyono T, Yamamoto M (2011) NRF2 mutation confers malignant potential and resistance to chemoradiation therapy in advanced esophageal squamous cancer. Neoplasia 13(9):864–873

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shih AY, Johnson DA, Wong G, Kraft AD, Jiang L, Erb H, Johnson JA, Murphy TH (2003) Coordinate regulation of glutathione biosynthesis and release by Nrf2-expressing glia potently protects neurons from oxidative stress. J Neurosci 23(8):3394–3406

    CAS  PubMed  Google Scholar 

  • Singh A, Misra V, Thimmulappa RK, Lee H, Ames S, Hoque MO, Herman JG, Baylin SB, Sidransky D, Gabrielson E, Brock MV (2006) Dysfunctional KEAP1–NRF2 interaction in non-small-cell lung cancer. PLoS Med 3(10):e420

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Sirota R, Gibson D, Kohen R (2015) The role of the catecholic and the electrophilic moieties of caffeic acid in Nrf2/Keap1 pathway activation in ovarian carcinoma cell lines. Redox Biol 4:48–59

    Article  CAS  PubMed  Google Scholar 

  • Slocum SL, Kensler TW (2011) Nrf2: control of sensitivity to carcinogens. Arch Toxicol 85(4):273–284

    Article  CAS  PubMed  Google Scholar 

  • Son TG, Camandola S, Mattson MP (2008) Hormetic dietary phytochemicals. Neuromol Med 10(4):236–246

    Article  CAS  Google Scholar 

  • Stogios PJ, Privé GG (2004) The BACK domain in BTB-kelch proteins. Trends Biochem Sci 29(12):634–637

    Article  CAS  PubMed  Google Scholar 

  • Sugamura K, Keaney JF Jr (2011) Reactive oxygen species in cardiovascular disease. Free Radic Biol Med 51(5):978–992

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sun Z, Wu T, Zhao F, Lau A, Birch CM, Zhang DD (2011) KPNA6 (Importin α7)-mediated nuclear import of Keap1 represses the Nrf2-dependent antioxidant response. Mol Cell Biol 31(9):1800–1811

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tagde A, Singh H, Kang MH, Reynolds CP (2014) The glutathione synthesis inhibitor buthionine sulfoximine synergistically enhanced melphalan activity against preclinical models of multiple myeloma. Blood Cancer J 4:e229

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tagde A, Rajabi H, Bouillez A, Alam M, Gali R, Bailey S, Tai YT, Hideshima T, Anderson K, Avigan D, Kufe D (2016a) MUC1-C drives MYC in multiple myeloma. Blood 127(21):2587–2597

    Article  CAS  PubMed  Google Scholar 

  • Tagde A, Rajabi H, Stroopinsky D, Gali R, Alam M, Bouillez A, Kharbanda S, Stone R, Avigan D, Kufe D (2016b) MUC1-C induces DNA methyltransferase 1 and represses tumor suppressor genes in acute myeloid leukemia. Oncotarget. doi:10.18632/oncotarget.9777

  • Taguchi K, Motohashi H, Yamamoto M (2011) Molecular mechanisms of the Keap1–Nrf2 pathway in stress response and cancer evolution. Genes Cells 16(2):123–140

    Article  CAS  PubMed  Google Scholar 

  • Takahashi H, Jin C, Rajabi H, Pitroda S, Alam M, Ahmad R, Raina D, Hasegawa M, Suzuki Y, Tagde A, Bronson RT (2015) MUC1-C activates the TAK1 inflammatory pathway in colon cancer. Oncogene 34(40):5187–5197

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tanigawa S, Fujii M, Hou DX (2007) Action of Nrf2 and Keap1 in ARE-mediated NQO1 expression by quercetin. Free Radic Biol Med 42(11):1690–1703

    Article  CAS  PubMed  Google Scholar 

  • Tayek JA, Kalantar-Zadeh K (2013) The extinguished BEACON of bardoxolone: not a Monday morning quarterback story. Am J Nephrol 37(3):208–211

    Article  PubMed  PubMed Central  Google Scholar 

  • Tong KI, Padmanabhan B, Kobayashi A, Shang C, Hirotsu Y, Yokoyama S, Yamamoto M (2007) Different electrostatic potentials define ETGE and DLG motifs as hinge and latch in oxidative stress response. Mol Cell Biol 27(21):7511–7521

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Turrens JF (2003) Mitochondrial formation of reactive oxygen species. J Physiol 552(2):335–344

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Venci JV, Gandhi MA (2013) Dimethyl fumarate (Tecfidera): a new oral agent for multiple sclerosis. Ann Pharmacother 47(12):1697–1702

    Article  CAS  PubMed  Google Scholar 

  • Walker FO (2007) Huntington’s disease. Lancet 369(9557):218–228

    Article  CAS  PubMed  Google Scholar 

  • Wang R, An J, Ji F, Jiao H, Sun H, Zhou D (2008) Hypermethylation of the Keap1 gene in human lung cancer cell lines and lung cancer tissues. Biochem Biophys Res Commun 373(1):151–154

    Article  CAS  PubMed  Google Scholar 

  • Wang W, Kang J, Li H, Su J, Wu J, Xu Y, Yu H, Xiang X, Yi H, Lu Y, Sun L (2013) Regulation of endoplasmic reticulum stress in rat cortex by p62/ZIP through the Keap1–Nrf2–ARE signalling pathway after transient focal cerebral ischaemia. Brain Inj 27(7–8):924–933

    Article  PubMed  Google Scholar 

  • Xu H, Zhou YL, Zhang XY, Lu P, Li GS (2010) Activation of PERK signaling through fluoride-mediated endoplasmic reticulum stress in OS732 cells. Toxicology 277(1):1–5

    Article  CAS  PubMed  Google Scholar 

  • Yamazaki H, Tanji K, Wakabayashi K, Matsuura S, Itoh K (2015) Role of the Keap1/Nrf2 pathway in neurodegenerative diseases. Pathol Int 65(5):210–219

    Article  CAS  PubMed  Google Scholar 

  • Yang C, Zhang X, Fan H, Liu Y (2009) Curcumin upregulates transcription factor Nrf2, HO-1 expression and protects rat brains against focal ischemia. Brain Res 1282:133–141

    Article  CAS  PubMed  Google Scholar 

  • Yu X, Kensler T (2005) Nrf2 as a target for cancer chemoprevention. Mutat Res 591(1–2):93–102

    Article  CAS  PubMed  Google Scholar 

  • Yu S, Khor TO, Cheung KL, Li W, Wu TY, Huang Y, Foster BA, Kan YW, Kong AN (2010) Nrf2 expression is regulated by epigenetic mechanisms in prostate cancer of TRAMP mice. PLoS One 5(1):e8579

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Zhang DD (2013) Bardoxolone brings Nrf2-based therapies to light. Antioxid Redox Signal 19(5):517–518

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Zhang M, An C, Gao Y, Leak RK, Chen J, Zhang F (2013) Emerging roles of Nrf2 and phase II antioxidant enzymes in neuroprotection. Prog Neurobiol 100:30–47

    Article  CAS  PubMed  Google Scholar 

  • Zhao X, Sun G, Zhang J, Strong R, Dash PK, Kan YW, Grotta JC, Aronowski J (2007) Transcription factor Nrf2 protects the brain from damage produced by intracerebral haemorrhage. Stroke 38(12):3280–3286

    Article  CAS  PubMed  Google Scholar 

  • Zhuang C, Narayanapillai S, Zhang W, Sham YY, Xing C (2014) Rapid identification of Keap1–Nrf2 small-molecule inhibitors through structure-based virtual screening and hit-based substructure search. J Med Chem 57(3):1121–1126

    Article  CAS  PubMed  Google Scholar 

  • Zipper LM, Mulcahy RT (2002) The Keap1 BTB/POZ dimerization function is required to sequester Nrf2 in cytoplasm. J Biol Chem 277(39):36544–36552

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

BP is grateful to the Indian Council of Medical Research (ICMR) (no. 001/101/2015/00787) and Department of Science and Technology, SERB (no. SR/SO/BB-0108/2012), Government of India, India for the financial support.

Author information

Author notes

    Authors and Affiliations

    1. Department of Biophysics, National Institute of Mental Health and Neurosciences (NIMHANS), Hosur Road, Bangalore, 560029, India

      Prashant Deshmukh, Sruthi Unni, Gopinatha Krishnappa & Balasundaram Padmanabhan

    Authors
    1. Prashant Deshmukh
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Sruthi Unni
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Gopinatha Krishnappa
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Balasundaram Padmanabhan
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Balasundaram Padmanabhan.

    Ethics declarations

    Conflict of interest

    Prashant Deshmukh declares that he has no conflicts of interest. Sruthi Unni declares that she has no conflicts of interest. Gopinath Krishnappa declares that he has no conflicts of interest. Balasundaram Padmanabhan declares that he has no conflicts of interest.

    Ethical approval

    This article does not contain any studies with human participants or animals performed by any of the authors.

    Additional information

    Prashant Deshmukh and Sruthi Unni contributed equally to this work.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Deshmukh, P., Unni, S., Krishnappa, G. et al. The Keap1–Nrf2 pathway: promising therapeutic target to counteract ROS-mediated damage in cancers and neurodegenerative diseases. Biophys Rev 9, 41–56 (2017). https://doi.org/10.1007/s12551-016-0244-4

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s12551-016-0244-4

    Keywords

    Search

    Navigation