TargetingAutophagyinCancer:RecentAdvancesandFutureDirectionsRaviK.Amaravadi1,AlecC.Kimmelman2,JayantaDebnath31AbramsonCancerCenterandtheDepartmentofMedicine,UniversityofPennsylvania,Philadelphia,Pennsylvania.2DepartmentofRadiationOncology,PerlmutterCancerCenter,NewYorkUniversitySchoolofMedicine,NewYork,NewYork.3DepartmentofPathology,UniversityofCalifornia,SanFrancisco,California.AbstractAutophagy,amultisteplysosomaldegradationpathwaythatsupportsnutrientrecyclingandmetabolicadaptation,hasbeenimplicatedasaprocessthatregulatescancer.Althoughautophagyinductionmaylimitthedevelopmentoftumors,evidenceinmousemodelsdemonstratesthatautophagyinhibitioncanlimitthegrowthofestablishedtumorsandimproveresponsetocancertherapeutics.Certaincancergenotypesmaybeespeciallypronetoautophagyinhibition.Differentstrategiesforautophagymodulationmaybeneededdependingonthecancercontext.Here,wereviewnewadvancesinthemolecularcontrolofautophagy,theroleofselectiveautophagyincancer,andtheroleofautophagywithinthetumormicroenvironmentandtumorimmunity.Wealsohighlightclinicaleffortstorepurposelysosomalinhibitors,suchashydroxychloroquine,asanticanceragentsthatblockautophagy,aswellasthedevelopmentofmorepotentandspecificautophagyinhibitorsforcancertreatment,andreviewfuturedirectionsforautophagyresearch.INTRODUCTIONMacroautophagy(hereafterreferredtoautophagy)istheprocessbywhichcellsformdouble-membranedautophagicvesicles(AV)thatsequesterorganellesandproteinsandtargetthemfordegradationinthelysosome.Althoughitwasoriginallyviewedasa“bulkdegradation”processactivatedbycellularstarvation,newfindingsdemonstratethatautophagycanalsobeahighlyselectivequality-controlmechanismthatregulateslevelsofspecificorganellesandproteins.Incancer,autophagymayplayaroleinlimitingtheearlieststagesoftumorigenesis;however,thereisgrowingevidencethat,inestablishedcancers,CorrespondingAuthor:RaviK.Amaravadi,UniversityofPennsylvania,8thFloorBRB,421CurieBoulevard,Philadelphia,PA19104.Phone:215-796-5159;Fax:215-349-8550;Ravi.amaravadi@penn...
