Statins inhibit T‐acute lymphoblastic leukemia cell adhesion and migration through Rap1b

Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society

关键词: T‐;    ALL;    prenylation;    GTPase;   

DOI  :  10.1189/jlb.0810441

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

StatinsareknowntoinhibitsignalingofRassuperfamilyGTPasesandreduceTcelladhesiontoICAM‐1.Here,weaddressthehypothesisthatstatinsaffectTcelladhesionandmigrationbymodulatingthefunctionofspecificGTPases.Statinsinhibitthesynthesisofmevalonicacid,whichisrequiredforfarnesylandgeranylgeranylisoprenoidsynthesis.RassuperfamilyGTPasesarepost‐translationallyisoprenylatedtofacilitatetheiranchoragetomembranes,wheretheyfunctiontostimulatesignaltransductionprocesses.Wedemonstratethat1μMstatininhibitstheadhesion,migration,andchemotaxisoftheT‐ALLcelllineCCRF‐CEMandTEMofCCRF‐CEMandPEERT‐ALLcells,buthigherstatinconcentrationsareneededtoinhibitadhesionofprimaryTcells.SimilareffectsareobservedfollowingtreatmentwithGGTI‐298orRNAinterference‐mediatedknockdownofRap1bbutnotRap1a,Rac1,Rac2,RhoA,orCdc42.StatinsalsoalterRap1activityandRap1blocalization.Rap1levelsarehigherinprimaryTcellsthanT‐ALLcells,whichcouldexplaintheirreducedsensitivitytostatins.TheseresultsdemonstrateforthefirsttimethatthecloselyrelatedRap1aandRap1bisoformshavedifferentfunctionsandsuggestthatstatinsorRap1bdepletioncouldbeusedtoreducetissueinvasioninT‐ALL...

【 授权许可】

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