SB202190-Induced Cell Type-Specific Vacuole Formation and Defective Autophagy Do Not Depend on p38 MAP Kinase Inhibition 英文参考文献.docVIP

SB202190-InducedCellType-SpecificVacuoleFormation andDefectiveAutophagyDoNotDependonp38MAP KinaseInhibition ManojB.Menon,AlexeyKotlyarov,MatthiasGaestel* InstituteofBiochemistry,HannoverMedicalSchool,Hannover,Germany Abstract SB202190, a widely used inhibitor of p38 MAPKa and b, was recently described to induce autophagic vacuoles and cell deathincolonandovariancancercellslinesand,therefore,thiseffectwassupposedtobespecificfortransformedcellsand toopentherapeuticoptions.Here,wedemonstratethatSB202190andthestructurallyrelatedinhibitorSB203580induce pro-autophagicgeneexpressionandvacuoleformationinvariouscancerandnon-cancercelllinesofhuman,rat,mouse andhamsterorigin.Thiseffectseemstoinducedefectiveautophagyleadingtotheaccumulationofacidicvacuoles,p62 proteinandlipidconjugatedLC3.Usingfurtherp38inhibitorsweshowthatp38MAPKinhibitionisnotsufficientforthe autophagic response. In line with these results, expression of a SB202190-resistant mutant of p38a, which significantly increasesactivityofthep38pathwayunderinhibitoryconditions,doesnotblockSB202190-dependentvacuoleformation, indicatingthatlackofp38aactivityisnotnecessaryforthiseffect.Obviously,theinductionofautophagicvacuoleformation bySB203580andSB202190isduetooff-targeteffectsoftheseinhibitorsonpost-translationalproteinmodifications,such asphosphorylationoftheMAPKsERK1/2andJNK1/2,ribosomalproteinS6,andPKB/Akt.Interestingly,thePI3K-inhibitor wortmannininducestransientvacuoleformationindicatingthatthePI3K-PKB/Akt-mTORpathwayisessentialforpreventing autophagy and that cross-inhibition of this pathway by SB202190 could be the reason for the early part of the effect observed. Citation:MenonMB,KotlyarovA,GaestelM(2011)SB202190-InducedCellType-SpecificVacuoleFormationandDefectiveAutophagyDoNotDependonp38 MAPKinaseInhibition.PLoSONE6(8):e23054.doi:10.1371/journal.pone.0023054 Editor:HarmKampinga,UniversityMedicalCenterGroningen,TheNetherlands ReceivedMay9,2011;AcceptedJuly5,2011;PublishedAugust10,2011 Copyright: ? 2011 Meno