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《Identification, Mechanism of Action, and Antitumor Activityof a Small Molecule Inhibitor of Hippo, TGF-b, and WntSignaling Pathways鉴定、作用机制和Antitumor活性 小分子抑制剂HIPPO、TGF-B和Wnt 信号通路》由会员上传分享，免费在线阅读，更多相关内容在学术论文-天天文库。
1、PublishedOnlineFirstApril2,2014;DOI:10.1158/1535-7163.MCT-13-0918MolecularCancerSmallMoleculeTherapeuticsTherapeuticsIdentification,MechanismofAction,andAntitumorActivityofaSmallMoleculeInhibitorofHippo,TGF-b,andWntSignalingPathways13231DipanjanBasu,RobertLetta
2、n,KrishnanDamodaran,SusanStrellec,MiguelReyes-Mugica,and1AbdelhadiRebbaaAbstractEmbryonicsignalingpathways,inparticularthosemediatedbyWntandTGF-b,areknowntoplaykeyrolesintumorprogressionthroughtheinductionofepithelialmesenchymaltransition(EMT).Theirsimultaneou
3、stargetingcouldthereforerepresentadesirableanticancerstrategy.OnthebasisofrecentfindingsthatbothWntandTGF-bassociatedpathwaysareregulatedbyHipposignalinginmammaliancells,wereasonedthattargetingthelatterwouldbemoreeffectiveininhibitingEMT.Inasearchforsuchinhibit
4、ors,weidentifiedasmallmolecule(C19)withremarkableinhibitoryactivitynotonlyagainstHippo,butalsoagainstWntandTGF-bpathways.C19inhibitedcancercellmigration,proliferation,andresistancetodoxorubicininvitro,andexertedstrongantitumoractivityinamousetumormodel.Mechanis
5、tically,C19inducedGSK3-bmediateddegradationoftheHippotransducerTAZ,throughactivationoftheHippokinasesMst/LatsandthetumorsuppressorkinaseAMPKupstreamofthedegradationcomplex.Overall,thisstudyidentifiedC19asamulti-EMTpathwayinhibitorwithauniquemechanismofaction.Th
6、efindingsthatbothAMPKandMst/LatsmediatetheantitumoractivityofC19shedlightonapotentialcross-talkbetweenmetabolicandorgansizecontrolpathwaysinregulatingcancerprogression.Bysimultaneouslytargetingthesetwopathways,C19mayrepresentanewtypeofagentstosuppresscancerprog
7、ressionand/oritsrecurrence.MolCancerTher;13(6);145767.Ó2014AACR.Introductionenchymal-likestateofcancercellsisbelievedtoconfernotonlyinvasiveability,butalsoprotectionfromcelldeath,Thedevelopmentofsolidtumorsimplicatesaseriesofimmuneescape,andresistancetotherapy
8、(9).Onthebasisintrinsicandextrinsiceventsthatpromptcellstoprolif-ofthis,approachestoinhibitEMTmayholdgreatpromiseerateoutofcontrolandtoacquiresurvivalandinvasiveforcancertreatment.
