《Identification, Mechanism of Action, and Antitumor Activityof a Small Molecule Inhibitor of Hippo, TGF-b, and WntSignaling Pathways鑒定、作用機(jī)制和Antitumor活性 小分子抑制劑HIPPO、TGF-B和Wnt 信號(hào)通路》由會(huì)員上傳分享，免費(fèi)在線閱讀，更多相關(guān)內(nèi)容在學(xué)術(shù)論文-天天文庫(kù)。

1、PublishedOnlineFirstApril2,2014;DOI:10.1158/1535-7163.MCT-13-0918MolecularCancerSmallMoleculeTherapeuticsTherapeuticsIdenti?cation,MechanismofAction,andAntitumorActivityofaSmallMoleculeInhibitorofHippo,TGF-b,andWntSignalingPathways13231DipanjanBasu,RobertLetta

2、n,KrishnanDamodaran,SusanStrellec,MiguelReyes-Mugica,and1AbdelhadiRebbaaAbstractEmbryonicsignalingpathways,inparticularthosemediatedbyWntandTGF-b,areknowntoplaykeyrolesintumorprogressionthroughtheinductionofepithelialmesenchymaltransition(EMT).Theirsimultaneou

3、stargetingcouldthereforerepresentadesirableanticancerstrategy.Onthebasisofrecent?ndingsthatbothWntandTGF-bassociatedpathwaysareregulatedbyHipposignalinginmammaliancells,wereasonedthattargetingthelatterwouldbemoreeffectiveininhibitingEMT.Inasearchforsuchinhibit

4、ors,weidenti?edasmallmolecule(C19)withremarkableinhibitoryactivitynotonlyagainstHippo,butalsoagainstWntandTGF-bpathways.C19inhibitedcancercellmigration,proliferation,andresistancetodoxorubicininvitro,andexertedstrongantitumoractivityinamousetumormodel.Mechanis

5、tically,C19inducedGSK3-bmediateddegradationoftheHippotransducerTAZ,throughactivationoftheHippokinasesMst/LatsandthetumorsuppressorkinaseAMPKupstreamofthedegradationcomplex.Overall,thisstudyidenti?edC19asamulti-EMTpathwayinhibitorwithauniquemechanismofaction.Th

6、e?ndingsthatbothAMPKandMst/LatsmediatetheantitumoractivityofC19shedlightonapotentialcross-talkbetweenmetabolicandorgansizecontrolpathwaysinregulatingcancerprogression.Bysimultaneouslytargetingthesetwopathways,C19mayrepresentanewtypeofagentstosuppresscancerprog

7、ressionand/oritsrecurrence.MolCancerTher;13(6);145767.ó2014AACR.Introductionenchymal-likestateofcancercellsisbelievedtoconfernotonlyinvasiveability,butalsoprotectionfromcelldeath,Thedevelopmentofsolidtumorsimplicatesaseriesofimmuneescape,andresistancetotherapy

8、(9).Onthebasisintrinsicandextrinsiceventsthatpromptcellstoprolif-ofthis,approachestoinhibitEMTmayholdgreatpromiseerateoutofcontrolandtoacquiresurvivalandinvasiveforcancertreatment.