Autophagy Suppresses RIP Kinase-Dependent Necrosis Enabling Survival to mTOR Inhibition 英文参考文献.docVIP
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Autophagy Suppresses RIP Kinase-Dependent Necrosis Enabling Survival to mTOR Inhibition 英文参考文献
AutophagySuppressesRIPKinase-DependentNecrosis
EnablingSurvivaltomTORInhibition
KevinBray1,RobinMathew1,2,AlexandriaLau3,JurreJ.Kamphorst6,JingFan6,JimChen1,Hsin-YiChen1,
AnahitaGhavami1,MarkStein1,2,4,RobertS.DiPaola1,2,4,DonnaZhang3,JoshuaD.Rabinowitz6,
EileenWhite1,2,5
*
1TheCancerInstituteofNewJersey,NewBrunswick,NewJersey,UnitedStatesofAmerica,2UniversityofMedicineandDentistryofNewJersey,Piscataway,NewJersey,
United States of America, 3Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona, United States of America, 4Division of Medical
Oncology,UniversityofMedicineandDentistryofNewJersey,Piscataway,NewJersey,UnitedStatesofAmerica,5DepartmentofMolecularBiologyandBiochemistry,
RutgersUniversity,Piscataway,NewJersey,UnitedStatesofAmerica,6DepartmentofChemistry,Lewis-SiglerInstituteforIntegrativeGenomics,PrincetonUniversity,
Princeton,NewJersey,UnitedStatesofAmerica
Abstract
mTORinhibitorsareusedclinicallytotreatrenalcancerbutarenotcurative.Hereweshowthatautophagyisaresistance
mechanismofhumanrenalcellcarcinoma(RCC)celllinestomTORinhibitors.RCCcelllineshavehighbasalautophagythat
is required for survival to mTOR inhibition. In RCC4 cells, inhibition of mTOR with CCI-779 stimulates autophagy and
eliminates RIP kinases (RIPKs) and this is blocked by autophagy inhibition, which induces RIPK- and ROS-dependent
necroptosisinvitroandsuppressesxenograftgrowth.AutophagyofmitochondriaisrequiredforcellsurvivalsincemTOR
inhibition turns off Nrf2 antioxidant defense. Thus, coordinate mTOR and autophagy inhibition leads to an imbalance
betweenROSproductionanddefense,causingnecroptosisthatmayenhancecancertreatmentefficacy.
Citation: Bray K, Mathew R, Lau A, Kamphorst JJ, Fan J, et al. (2012) Autophagy Suppresses RIP Kinase-Dependent Necrosis Enabling Survival to mTOR
Inhibition.PLoSONE7(7):e41831.doi:10.1371/journal.pone.0041831
Editor:GianMariaFimia,IstitutoNazionaleperleMalattieInfettive,Italy
ReceivedMay3,2012;AcceptedJune25,2012;PublishedJuly26,2
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