Aciculatin Induces p53-Dependent Apoptosis via MDM2 Depletion in Human Cancer Cells In Vitro and In Vivo 英文参考文献.docVIP

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Aciculatin Induces p53-Dependent Apoptosis via MDM2 Depletion in Human Cancer Cells In Vitro and In Vivo 英文参考文献.doc

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Aciculatin Induces p53-Dependent Apoptosis via MDM2 Depletion in Human Cancer Cells In Vitro and In Vivo 英文参考文献

AciculatinInducesp53-DependentApoptosisviaMDM2 DepletioninHumanCancerCellsInVitroandInVivo Chin-YuLai1,An-ChiTsai2,Mei-ChuanChen1,Li-HsunChang1,Hui-LungSun1,Ya-LingChang1 ,Chien- ChihChen3,Che-MingTeng1*.,Shiow-LinPan2*. 1PharmacologicalInstitute,CollegeofMedicine,NationalTaiwanUniversity,Taipei,Taiwan,2InstituteofBiotechnologyandPharmaceuticalResearch,NationalHealth ResearchInstitutes,ZhunanTown,Taiwan,3DepartmentofBiotechnology,HungkuangUniversity,Taichung,Taiwan Abstract Aciculatin, a natural compound extracted from the medicinal herb Chrysopogon aciculatus, shows potent anti-cancer potency. This study is the first to prove that aciculatin induces cell death in human cancer cells and HCT116 mouse xenografts due to G1 arrest and subsequent apoptosis. The primary reason for cell cycle arrest and cell death was p53 accumulation followed by increased p21 level, dephosphorylation of Rb protein, PUMA expression, and induction of apoptoticsignalssuchascleavageofcaspase-9,caspase-3,andPARP.Wedemonstratedthatp53allele-null(2/2 )(p53-KO) HCT116 cells were more resistant to aciculatin than cells with wild-type p53 (+/+). The same result was achieved by knockingdownp53withsiRNAinp53wild-typecells,indicatingthatp53playsacrucialroleinaciculatin-inducedapoptosis. AlthoughDNAdamageisthemostcommoneventleadingtop53activation,wefoundonlyweakevidenceofDNAdamage afteraciculatintreatment.Interestingly,theaciculatin-induceddownregulationofMDM2,animportantnegativeregulator ofp53,contributedtop53accumulation.Theanti-canceractivityandimportanceofp53afteraciculatintreatmentwerealso confirmedintheHCT116xenograftmodels.Collectively,theseresultsindicatethataciculatintreatmentinducescellcycle arrest and apoptosis via inhibition of MDM2 expression, thereby inducing p53 accumulation without significant DNA damageandgenometoxicity. Citation:LaiC-Y,TsaiA-C,ChenM-C,ChangL-H,SunH-L,etal.(2012)AciculatinInducesp53-DependentApoptosisviaMDM2DepletioninHumanCancerCells InVitroandInVivo.PLoSONE7(8):e4219