Screen for Chemical Modulators of Autophagy Reveals Novel Therapeutic Inhibitors of mTORC1 Signaling 英文参考文献.docVIP

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Screen for Chemical Modulators of Autophagy Reveals Novel Therapeutic Inhibitors of mTORC1 Signaling 英文参考文献.doc

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Screen for Chemical Modulators of Autophagy Reveals Novel Therapeutic Inhibitors of mTORC1 Signaling 英文参考文献

ScreenforChemicalModulatorsofAutophagyReveals NovelTherapeuticInhibitorsofmTORC1Signaling ArunaD.Balgi1.,BrunoD.Fonseca1.,ElizabethDonohue1,TrevorC.F.Tsang1,PatrickLajoie2¤, ChristopherG.Proud3,IvanR.Nabi2,MichelRoberge1* 1Department ofBiochemistryandMolecularBiology,UniversityofBritishColumbia,Vancouver,BritishColumbia,Canada, 2DepartmentofCellularandPhysiological Sciences,UniversityofBritishColumbia,Vancouver,BritishColumbia,Canada,3SchoolofBiologicalSciences,UniversityofSouthampton,Southampton,UnitedKingdom Abstract Background:Mammaliantargetofrapamycincomplex1(mTORC1)isaproteinkinasethatrelaysnutrientavailabilitysignals tocontrolnumerouscellularfunctionsincludingautophagy,aprocessofcellularself-eatingactivatedbynutrientdepletion. Addressing the therapeutic potential of modulating mTORC1 signaling and autophagy in human disease requires active chemicalswithpharmacologicallydesirableproperties. Methodology/PrincipalFindings:Usinganautomatedcell-basedassay,wescreenedacollectionof.3,500chemicalsand identifiedthreeapproveddrugs(perhexiline,niclosamide,amiodarone)andonepharmacologicalreagent(rottlerin)capable ofrapidlyincreasingautophagosomecontent.Biochemicalassaysshowedthatthefourcompoundsstimulateautophagy and inhibit mTORC1 signaling in cells maintained in nutrient-rich conditions. The compounds did not inhibit mTORC2, which also contains mTOR as a catalytic subunit, suggesting that they do not inhibit mTOR catalytic activity but rather inhibitsignalingtomTORC1.mTORC1inhibitionandautophagosomeaccumulationinducedbyperhexiline,niclosamideor rottlerinwererapidlyreversedupondrugwithdrawalwhereasamiodaroneinhibitedmTORC1essentiallyirreversibly.TSC2, anegativeregulatorofmTORC1,wasrequiredforinhibitionofmTORC1signalingbyrottlerinbutnotformTORC1inhibition byperhexiline,niclosamideandamiodarone.Transientexposureofimmortalizedmouseembryofibroblaststothesedrugs wasnottoxicinnutrient-richconditionsbutledtorapidcelldeathbyapoptosisinstarvationconditions,byamechanism de