Nrf2在腫瘤中的雙重作用

TheDualRoleofNrf2in

CancerTheNrf2field–exponentialgrowthin

publicationsDiscoveryoftheAntioxidantResponsiveElement

(ARE)Surh,NatRevCancer3:768,

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GlutathioneS-transferase(GST)Glutamate-cysteineligase(GCLM,GCLC)UDP-glucuronosyltransferase(UGT)NAD(P)Hquinoneoxidoreductase

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5361Nrf2activatesARE-dependentgenesmRNAPhase

II

genes (GST,NQO1,

GCS)AREMaf Nrf2InNrf2-/-

miceDecreasedbasalexpressionofthe

phase-IIdetoxificationenzymesIncreasedsensitivitytochemical

carcinogensImpairedinductionoftheseenzymesbychemopreventivecompoundsLossofanti-cancerefficacyofchemopreventivecompoundsRamos-Gomezetal.,ProcNatlAcadSciUSA98:3410,

2000Itohetal.,GeneDev13(1):76,1999;McMahonetal.,JBiolChem281:24756,2006Tongetal.,MolCellBiol26:2887,2006;Tongetal.,MolCellBiol27:7511,

2007Keap1-Nrf2interactionThehingeandlatch

modelNrf2regulationbyKeap1(Canonical;Keap1-C151

dependent)ZhangandHannink,MolCellBiol23:8137,2003Zhangetal.,MolCellBiol24:10941,

2004JaramilloandZhang,GenesDev27(20):2179,

2013Cys-Cys-Cys-Cys-Nrf2UE2Cul3Rbx1DLGETGECys-Cys-Cys-Cys-Cys-Cys-E2Cul3Rbx1Nrf2UUU

UU

UDLGETGECys-Cys-Cys-Cys-Cys-Cys-BasalBasalCul3E2Rbx1Cys-Cys- UNrf2DLGETGEInducedNrf2Nrf2Nrf2MafNrf2ARE5’-RTGABNNNGCR-3’5’-TMANNRTGABNNNGCR-3’NQO1GCLMHMOX-1AKR1C1ThedualroleofNrf2in

CancerTheprotectiveroleofNrf2against

diseasesThe“darkside”ofNrf2ConstitutiveactivationofNrf2in

tumorsPoorprognosisandenhanced

resistanceAcceleratestumor

metastasisNrf2inhibitors:overcomeresistanceOHCH3BHTN C SSO3H

CSulforaphaneN C SPhenylIsothiocyanateN C SPhenethylIsothiocyanateN C SBenzylIsothiocyanateSH2CN CAllyl

Isothiocyanate1-cyano-2,3-epithiopropane1-cyano-3,4-epithiobutane1-cyano-4,5-epithiopentane

NS

NS

NS

HOOHOHOOHOH3COHOOOHOCH3OOOOOOCH3H3CCH3CH3H3C CH3OHOHOHOCCurcuminCoumarinOH OQuercetinCarnosolDimethyl

fumarateOOCaffeicacidphenethyl

esterOHOH3OHOHNCH3CH3CH33H

COCHBHAEthoxyquinNrf2activators:targeting

Keap1Hayes,et.al.AntioxidRedoxsignaling,

2010Oxidative

StressOH·HOClNOH2O2

ROOHONOO–1O2O2·-CancerDiabeticcomplicationsCardiovasculardiseasesLungdiseasesInflammatorydiseasesKidneydiseasesSkinDisorderLiverdiseasesNeurodegenerativediseasesEyediseasesAgingTheprotectiveroleof

Nrf2Thedarksideof

Nrf2ConstitutiveactivationofNrf2intumorsPoorprognosisandenhancedresistanceAcceleratestumor

metastasisNrf2inhibitors:overcomeresistanceIn

Keap1Typeof

Cancer12cellline/54

NSCLCFrequencyKelch

/LinkerCelllines+

NSCLC50%/

19%LOH

(19p13.2)Celllines+

NSCLC61%/

41%Singhetal.,PLoSMed3:e420,

2006ConstitutiveactivationofNrf2in

tumorsDysregulationoftheNrf2-Keap1-Cul3

complexTongetal.,MolCellBiol26:2887,2006McMahonetal.,JBiolChem281:24756,

2006Lawrenceetal.,Nature505,

2014ConstitutiveactivationofNrf2in

tumorsDysregulationoftheNrf2-Keap1-Cul3

complexLawrenceetal.,Nature505,

2014DualroleofNrf2in

CancerTypeCases(117)%Nrf2+CasesCH200EEC5128ESC4689Jiangetal.,CancerRes70:5486,

2010CH:Complex

HyperplasiaEEC:EndometrialEndometrioidESC:Endometrial

SerousNrf2expressioninendometrialcancerDPP-4i,saxagliptin,sitagliptin,α-lipoicacid

(ALA)NRF2activationbyantidiabeticagentsacceleratestumor

metastasisWangetal.,scitranslmed,

2016CtlSax SitHCTHuHBruceaJavanica(L)

Merr.BrusatolRenetal.,ProcNatlAcadSciUSA108:1433,

2011BrusatolinhibitstheNrf2

pathwayBrusatolenhancestheefficacyof

cisplatinTaoetal.,CancerResearch74

(24):7431,2014CCSP-Cre;LSL-KrasG12DA549

xenograftRenetal.,ProcNatlAcadSci

USA108:1433,2011Tomasetti/Vogelstein’s“badluck”

theoryEnvironmental

factorsInherited

predispositionsRandommutationsduringDNAreplicationinnormalstem

cellsTomasettiandVogelstein,Science347:78,

2015TheroleofNrf2in

CancerGenetic

predisposition(CCSP-Cre;LSL-KrasG12D)Chemical

carcinogen(vinyl

carbamate)Unpublished

dataTheroleofNrf2in

CancerGenetic

predisposition(CCSP-Cre;LSL-KrasG12D)Chemical

carcinogen(vinyl

carbamate)Unpublished

dataTheroleofNrf2in

CancerGenetic

predisposition(CCSP-Cre;LSL-KrasG12D)Chemic