癌细胞得瑟mmc2

ArticleCharacterizationofaSteroidReceptorCoactivatorSmallMoleculeStimulatorthatOverstimulatesCancerCellsandLeadstoCellStressandDeathGraphicalAbstractHighlightsdThesmallmoleculecompoundMCB-613super-stimulatesSRCtranscriptionalactivitydAcutehyper-activationofSRCsbyMCB-613leadstoaberrantcellularstressdMCB-613selectivelykillscancercellsandinhibitstumorgrowthinvivodOver-activationofSRCsisapotentialalternativestrategyforcancertherapyAuthorsLeiWang,YangYu,Dar-ChoneChow,...,JianmingXu,DavidM.Lonard,BertW.O’[e-mail](D.M.L.),[e-mail](B.W.O.)InBriefWangetal.identifyMCB-613asapotentsteroidreceptorcoactivator(SRC)smallmoleculestimulator.Theyshowthat,paradoxically,acutesuper-activationofSRCsspecificallyandeffectivelykillscancercellsbyinducingaberrantcellularstress,suggestinganalternativestrategyagainstcancer.Wangetal.,2015,CancerCell28,240–252August10,2015ª2015ElsevierInc.*andBertW.O’Malley1,*1DepartmentofMolecularandCellularBiology,BaylorCollegeofMedicine,Houston,TX77030,USA2DepartmentofPharmacology,BaylorCollegeofMedicine,Houston,TX77030,USA3DepartmentofEpigeneticsandMolecularCarcinogenesis,TheUniversityofTexasMDAndersonCancerCenter,Houston,TX77030,USA*Correspondence:[e-mail](D.M.L.),[e-mail](B.W.O.)(SRC-1,SRC-2,andSRC-3)representemergingtargetsincancertherapeutics.High-throughputscreeningforSRCsmallmoleculeinhibitors(SMIs)uncoveredMCB-613asapotentSRCsmallmolecule‘‘stimulator’’(SMS).WedemonstratethatMCB-613cansuper-stimulateSRCs’transcriptionalactivity.FurtherinvestigationrevealedthatMCB-613increasesSRCs’interactionswithothercoactivatorsandmarkedlyinducesERstresscoupledtothegenerationofreactiveoxygenspecies(ROS).BecausecancercellsoverexpressSRCsandrelyonthemforgrowth,weshowthatwecanexploitMCB-613toselectivelyinduceexcessivestressincancercells.Thissuggeststhatover-stimulatingtheSRConcogenicprogramcanbeaneffectivestrategytokillcancercells.INTRODUCTIONMembersofthep160steroidreceptorcoactivator(SRC)family,SRC-1/NCOA1,SRC-2/NCOA2/TIF2/GRIP1andSRC-3/NCOA3/AIB1/RAC3/ACTR/pCIPinteractwithnuclearreceptorsandothertranscriptionfactorstodrivetargetgeneexpressionwhilealsofunctioningasintegratorsofupstreamcellsignalingpathways(LonardandO’malley,2007).Althoughtheysharehomologywitheachother,theyhavedistinctandimportantrolesinmultiplephysiologicalprocesses,includinggrowthanddevelopment,reproduction,andmetabolism(Xuetal.,2009;YorkandO’Malley,2010).Allthreeproteinshavealsobeenfoundtobebroadlyinvolvedindifferentaspectsoftumorigen-esis.SRC-3isbestknownforitsoncogenicrole,anditsgeneisamplifiedin9.5%ofbreastcancers(Anzicketal.,1997),anditsmRNAhasbeenshowntobeoverexpressedindifferentbreastcancercohorts,oftenatthe50%levelorgreater(Anzicketal.,1997;Bourasetal.,2001;Glaeseretal.,2001;Zhaoetal.,2003).Clinically,SRC-3overexpressioninbreastcancercorre-lateswithlargertumorsize(Bautistaetal.,1998),highertumorgrade(Hudelistetal.,2003)andpoorsurvivalrates(Zhaoetal.,2003).DirectevidencesupportingSRC-3asabonafideoncogenecomesfromanMMTV-SRC-3transgenicmousemodelinwhichoverexpressionofSRC-3wassufficienttocausethespontaneousdevelopmentofmalignantmammarytumors(Torres-Arzayusetal.,2004).SRC-3overexpressionhasalsobeenobservedinendometrial(Kershahetal.,2004),ovarian(Bautistaetal.,1998),prostate(Gnanapragasametal.,2001),colorectal(Xieetal.,2005),gastric(Sakakuraetal.,2000),lung(Caietal.,2010),pancreatic(Henkeetal.,2004),andlivercan-cers(Wangetal.,2002).AdditionalinvitroandinvivostudieshavebolsteredtheimportanceofSRC-3intumorinitiation,progression,metastasis,anddrugresistance(Xuetal.,2009).SRC-1isalsooverexpressedinabout20%ofbreastcancersSignificanceBecauseoftheiressentialrolesintumorigenesis,SRCfamilycoactivatorshavebeenrecognizedrecentlyasimportanttar-getsforfuturecancertherapeutics.BecauseSRCproteinsintegrateanddrivekeyoncogenicpathwayscancercellsusetoachieveacceleratedgrowth,invasion,energymetabolism,andmetastasis,SRCSMIs/SMSsareexpectedtobeeffectiveagentstotreatcancers.AlthoughafewSRCSMIshavebeendescribed,herewereportthecharacterizationofanSRCSMS,MCB-613.Ourresultsrevealthatacutesuper-activationofSRCcoactivatorscanparadoxicallybuteffectivelykillcan-cercellsbyinducingaberrantcellularstress,suggestingthatover-stimulationoftheSRConcogenicprogramisanalterna-tiveapproachtoselectivelykillcancercellswhosecellularstressresponsepathwaysarealreadymaximallyengaged.240CancerCell28,240–252,August10,2015ª2015ElsevierInc.andispositivelycorrelatedwithERBB2expression,diseaserecurrence,andpoorsurvival(Flemingetal.,2004;Myersetal.,2004).IthasbeendemonstratedthatSRC-1playsacritica