Activation of the Akt Survival Pathway Contributes to TRAIL Resistance in Cancer Cells 英文参考文献.docVIP

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Activation of the Akt Survival Pathway Contributes to TRAIL Resistance in Cancer Cells 英文参考文献.doc

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Activation of the Akt Survival Pathway Contributes to TRAIL Resistance in Cancer Cells 英文参考文献

ActivationoftheAktSurvivalPathwayContributesto TRAILResistanceinCancerCells JingXu1,Jun-YingZhou1,Wei-ZenWei2,GenShengWu1* 1PrograminMolecularBiologyGenetics,KarmanosCancerInstitute,DepartmentofPathology,WayneStateUniversitySchoolofMedicine,Detroit,Michigan,United StatesofAmerica,2PrograminBreast Cancer,KarmanosCancerInstitute,DepartmentofImmunologyandMicrobiology,WayneStateUniversitySchoolofMedicine, Detroit,Michigan,UnitedStatesofAmerica Abstract The mechanism of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) resistance in cancer cells is not fully understood.Here,weshowthattheAktsurvivalpathwayplaysanimportantroleinTRAILresistanceinhumancancercells. Specifically,wefoundthatTRAILtreatmentactivatestheAktsurvivalpathwayandthatinhibitionofthispathwaybythe PI3KinhibitorLY294002orknockdownofAktsensitizesresistantcancercellstoTRAIL.SinceAktisnegativelyregulatedby the tumor suppressor PTEN, we examined the TRAIL sensitivity in PTEN knockdown mouse prostate epithelial cells and foundthatPTEN2/2cellsaremoreresistantthanPTEN+/+cellswhilethesensitivityofPTEN +/2 cellsfellinbetween.Further, +/+ weshowedthatoverexpressionofamutantPTENconfersTRAILresistanceinPTEN cells,supportingaroleofPTENin TRAILsensitivity.InTRAILresistantbreastT47Dcells,overexpressionofthemutantPTENfurtherincreasedtheirresistance toTRAIL.Takentogether,ourdataindicatethatinactivationoffunctionalPTENandtheconsequentactivationoftheAkt pathwaypreventsTRAIL-inducedapoptosis,leadingtoTRAILresistance.Therefore,ourresultssuggestthatTRAILresistance canbeovercomebytargetingPTENortheAktsurvivalpathwayincancercells. Citation:XuJ,ZhouJ-Y,WeiW-Z,WuGS(2010)ActivationoftheAktSurvivalPathwayContributestoTRAILResistanceinCancerCells.PLoSONE5(4):e10226. doi:10.1371/journal.pone.0010226 Editor:Dong-YanJin,UniversityofHongKong,HongKong ReceivedFebruary22,2010;AcceptedMarch19,2010;PublishedApril19,2010 Copyright:?2010Xuetal.Thisisanopen-accessarticledistributedunderthetermsoftheCreativeCommonsAttrib