Protein Kinase A Activity and Anchoring Are Required for Ovarian Cancer Cell Migration and Invasion 英文参考文献.docVIP

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Protein Kinase A Activity and Anchoring Are Required for Ovarian Cancer Cell Migration and Invasion 英文参考文献.doc

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Protein Kinase A Activity and Anchoring Are Required for Ovarian Cancer Cell Migration and Invasion 英文参考文献

ProteinKinaseAActivityandAnchoringAreRequiredfor OvarianCancerCellMigrationandInvasion AndrewJ.McKenzie1,2,ShirleyL.Campbell2¤,AlanK.Howe1,2* 1DepartmentofPharmacology,UniversityofVermontCollegeofMedicine,Burlington,Vermont,UnitedStatesofAmerica,2TheVermontCancerCenter,Universityof VermontCollegeofMedicine,Burlington,Vermont,UnitedStatesofAmerica Abstract Epithelial ovarian cancer (EOC) is the deadliest of the gynecological malignancies, due in part to its clinically occult metastasis.Therefore,understandingthemechanismsgoverningEOCdisseminationandinvasionmayprovidenewtargets forantimetastatictherapiesornewmethodsfordetectionofmetastaticdisease.ThecAMP-dependentproteinkinase(PKA) isoftendysregulatedinEOC.Furthermore,PKAactivityandsubcellularlocalizationbyA-kinaseanchoringproteins(AKAPs) areimportantregulatorsofcytoskeletaldynamicsandcellmigration.Thus,wesoughttostudytheroleofPKAandAKAP functioninbothEOCcellmigrationandinvasion.Usingtheplasmamembrane-directedPKAbiosensor,pmAKAR3,andan improvedmigration/invasionassay,weshowthatPKAisactivatedattheleadingedgeofmigratingSKOV-3EOCcells,and thatinhibitionofPKAactivityblocksSKOV-3cellmigration.Furthermore,weshowthatwhilethePKAactivitywithinthe leadingedgeofthesecellsismediatedbyanchoringoftype-IIregulatoryPKAsubunits(RII),inhibitionofanchoringofeither RIorRIIPKAsubunitsblockscellmigration.Importantly,wealsoshow–forthefirsttime–thatPKAactivityisup-regulated attheleadingedgeofSKOV-3cellsduringinvasionofathree-dimensionalextracellularmatrixand,asseenformigration, inhibition of either PKA activity or AKAP-mediated PKA anchoring blocks matrix invasion. These data are the first to demonstrate that the invasion of extracellular matrix by cancer cells elicits activation of PKA within the invasive leading edgeandthatbothPKAactivityandanchoringarerequiredformatrixinvasion.TheseobservationssuggestaroleforPKA andAKAPactivityinEOCmetastasis. Citation:McKenzieAJ,CampbellSL,HoweAK(2011)ProteinKinaseAActivityandAnchoringAreRequiredforOva