Double-Stranded RNA-Dependent Protein Kinase Regulates the Motility of Breast Cancer Cells 英文参考文献.docVIP

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Double-Stranded RNA-Dependent Protein Kinase Regulates the Motility of Breast Cancer Cells 英文参考文献.doc

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Double-Stranded RNA-Dependent Protein Kinase Regulates the Motility of Breast Cancer Cells 英文参考文献

Double-StrandedRNA-DependentProteinKinase RegulatestheMotilityofBreastCancerCells MeiXu1,GangChen1,SiyingWang1,2,MingjunLiao1,JacquelineA.Frank1,KimberlyA.Bower1, ZhuoZhang3,XianglinShi3,JiaLuo1* 1DepartmentofInternalMedicine,UniversityofKentuckyCollegeofMedicine,Lexington,Kentucky,UnitedStatesofAmerica,2PathophysiologicalDepartment,School of Basic Medicine, Anhui Medical University, Hefei, Anhui, China, 3Graduate Center for Toxicology, University of Kentucky College of Medicine, Lexington, Kentucky, UnitedStatesofAmerica Abstract Double-strandedRNA(dsRNA)-dependentproteinkinase(PKR)isaninterferon-inducedproteinkinasethatplaysacentral role in the anti-viral process. Due to its pro-apoptotic and anti-proliferative action, there is an increased interest in PKR modulationasananti-tumorstrategy.PKRisoverexpressedinbreastcancercells;however,theroleofPKRinbreastcancer cellsisunclear.Theexpression/activityofPKRappearsinverselyrelatedtotheaggressivenessofbreastcancercells. The current study investigated the role of PKR in the motility/migration of breast cancer cells. The activation of PKR by a synthesized dsRNA (PIC) significantly decreased the motility of several breast cancer cell lines (BT474, MDA-MB231 and SKBR3).PICinhibitedcellmigrationandblockedcellmembranerufflingwithoutaffectingcellviability.PICalsoinducedthe reorganizationoftheactincytoskeletonandimpairedtheformationoflamellipodia.TheseeffectsofPICwerereversedby the pretreatment of a selective PKR inhibitor. PIC also activated p38 mitogen-activated protein kinase (MAPK) and its downstreamMAPK-activatedproteinkinase2(MK2).PIC-inducedactivationofp38MAPKandMK2wasattenuatedbythe PKRinhibitorandthePKRsiRNA,butaselectivep38MAPKinhibitor(SB203580)orotherMAPKinhibitorsdidnotaffectPKR activity, indicatingthat PKR is upstream ofp38 MAPK/MK2. Cofilin is anactin severing proteinand regulates membrane ruffling,lamellipodiaformationandcellmigration.PICinhibitedcofilinactivitybyenhancingitsphosphorylationatSer3.PIC a