Resveratrol Inhibits Growth of Orthotopic Pancreatic Tumors through Activation of FOXO Transcription Factors 英文参考文献.docVIP

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Resveratrol Inhibits Growth of Orthotopic Pancreatic Tumors through Activation of FOXO Transcription Factors 英文参考文献.doc

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Resveratrol Inhibits Growth of Orthotopic Pancreatic Tumors through Activation of FOXO Transcription Factors 英文参考文献

ResveratrolInhibitsGrowthofOrthotopicPancreatic TumorsthroughActivationofFOXOTranscription Factors SanjitK.Roy1,QingheChen1¤,JunshengFu2,SharmilaShankar2,RakeshK.Srivastava1* 1DepartmentofPharmacology,ToxicologyandTherapeutics,andMedicine,TheUniversityofKansasCancerCenter,TheUniversityofKansasMedicalCenter,KansasCity, Kansas,UnitedStatesofAmerica,2DepartmentofPathologyandLaboratoryMedicine,TheUniversityofKansasCancerCenter,TheUniversityofKansasMedicalCenter, KansasCity,Kansas,UnitedStatesofAmerica Abstract Background:TheforkheadtranscriptionfactorsoftheOclass(FOXO)playadirectroleincellularproliferation,oxidative stress response, and tumorigenesis. The objectives of this study were to examine whether FOXOs regulate antitumor activitiesofresveratrolinpancreaticcancercellsinvitroandinvivo. Methodology/PrincipalFindings:Pancreaticcancercelllinesweretreatedwithresveratrol.Cellviability,colonyformation, apoptosisandcellcycleweremeasuredbyXTT,softagar,TUNELandflowcytometryassays,respectively. FOXOnuclear translocation,DNAbindingandtranscriptionalactivitiesweremeasuredbyfluorescencetechnique,gelshiftandluciferase assay, respectively. Mice were orthotopically implanted with PANC1 cells and orally gavaged with resveratrol. The components of PI3K and ERK pathways, FOXOs and their target gene expressions were measured by the Western blot analysis.Resveratrolinhibitedcellviabilityandcolonyformations,andinducedapoptosisthroughcaspase-3activationin four pancreatic cancer cell lines (PANC-1, MIA PaCa-2, Hs766T, and AsPC-1). Resveratrol induced cell cycle arrest by up- regulatingtheexpressionofp21/CIP1,p27/KIP1andinhibitingtheexpressionofcyclinD1.Resveratrolinducedapoptosisby up-regulatingBimandactivatingcaspase-3.ResveratrolinhibitedphosphorylationofFOXOs,andenhancedtheirnuclear translocation,FOXO-DNAbindingandtranscriptionalactivities.TheinhibitionofPI3K/AKTandMEK/ERKpathwaysinduced FOXOtranscriptionalactivityandapoptosis.Furthermore,deletionofFOXOgenesabrogatedresveratr