Sensitization of Glioma Cells to Tamoxifen-Induced Apoptosis by Pl3-Kinase Inhibitor through the GSK-3ββ-Catenin Signaling Pathway 英文参考文献.docVIP

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Sensitization of Glioma Cells to Tamoxifen-Induced Apoptosis by Pl3-Kinase Inhibitor through the GSK-3ββ-Catenin Signaling Pathway 英文参考文献.doc

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Sensitization of Glioma Cells to Tamoxifen-Induced Apoptosis by Pl3-Kinase Inhibitor through the GSK-3ββ-Catenin Signaling Pathway 英文参考文献

SensitizationofGliomaCellstoTamoxifen-Induced ApoptosisbyPl3-KinaseInhibitorthroughtheGSK-3b/b- CateninSignalingPathway CuixianLi1,ChunZhou1,ShaoguiWang1,YingFeng2,WeiLin1,SisiLin1,YingWang1,HeqingHuang1, PeiqingLiu1,Yong-GaoMu3*,XiaoyanShen1* 1LaboratoryofPharmacologyandToxicology,SchoolofPharmaceuticalSciences,SunYat-senUniversity,Guangzhou,China,2DepartmentofHistologyandEmbryology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China, 3Department of Neurosurgery/Neuro-oncology, Cancer Center, Sun Yat-sen University, Guangzhou,China Abstract Malignantgliomasrepresentoneofthemostaggressivetypesofcancersandtheirrecurrenceiscloselylinkedtoacquired therapeutic resistance. A combination of chemotherapy is considered a promising therapeutic model in overcoming therapeuticresistanceandenhancingtreatmentefficacy.Herein,weshowbycolonyformation,Hochest33342andTUNEL staining, as well as by flow cytometric analysis, that LY294002, a specific phosphatidylinositide-3-kinase (PI3K) inhibitor, enhancedsignificantlythesensitizationofatraditionalcytotoxicchemotherapeuticagent,tamoxifen-inducedapoptosisin C6gliomacells.ActivationofPI3KsignalingpathwaybyIGF-1protectedU251cellsfromapoptosisinducedbycombination treatment of LY294002 and tamoxifen. Interference of PI3K signaling pathway by PI3K subunit P85 siRNA enhanced the sensitization of U251 glioma cells to tamoxifen -induced apoptosis. By Western blotting, we found that combination treatmentshowedlowerlevelsofphosphorylatedAktSer473andGSK-3bSer9thanasingletreatmentofLY294002.Further,we showedasignificantdecreaseofnuclear b-cateninby combinationtreatment.Inresponsetotheinhibitionof b-catenin signaling, mRNA and protein levels of Survivin and the other three antiapoptotic genes Bcl-2, Bcl-xL, and Mcl-1 were significantlydecreasedbycombinationtreatment.Ourresultsindicated thatthesynergisticcytotoxiceffectofLY294002 andtamoxifenisachievedbytheinhibitionofGSK-3b/b-cateninsignalingpathway. Citation:LiC,Zhou