Androgen-Induced Cell Migration Role of Androgen ReceptorFilamin A Association 英文参考文献.docVIP

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Androgen-Induced Cell Migration Role of Androgen ReceptorFilamin A Association 英文参考文献.doc

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Androgen-Induced Cell Migration Role of Androgen ReceptorFilamin A Association 英文参考文献

Androgen-InducedCellMigration:RoleofAndrogen Receptor/FilaminAAssociation GabriellaCastoria1,LoredanaD’Amato1,AlessandraCiociola1,PiaGiovannelli1,TizianaGiraldi1, LeandraSepe3,GiovanniPaolella3,MariaVittoriaBarone2,AntimoMigliaccio1*,FerdinandoAuricchio1 1DipartimentodiPatologiaGenerale,IIUniversita`diNapoli,Napoli,Italy,2EuropeanLaboratoryfortheInvestigationofFoodInducedDisease,DipartimentodiPediatria, Universita` ‘FedericoII’,Napoli,Italy,3DipartimentodiBiochimicaeBiotecnologieMediche,Universita` ‘FedericoII’,Napoli,Italy Abstract Background: Androgen receptor (AR) controls male morphogenesis, gametogenesis and prostate growth as well as development of prostate cancer. These findings support a role for AR in cell migration and invasiveness. However, the molecularmechanisminvolvedinAR-mediatedcellmigrationstillremainselusive. Methodology/Principal Findings: Mouse embryo NIH3T3 fibroblasts and highly metastatic human fibrosarcoma HT1080 cellsharborlowlevelsoftranscriptionallyincompetentAR.Wenowreportthat,throughextranuclearaction,ARtriggers migrationofbothcelltypesuponstimulationwithphysiologicalconcentrationsoftheandrogenR1881.Weanalyzedthe initial eventsleading toandrogen-induced cellmigrationandobserved thatchallengingNIH3T3 cells with10nM R1881 rapidly induces interaction of AR with filamin A (FlnA) at cytoskeleton. AR/FlnA complex recruits integrin beta 1, thus activatingitsdependentcascade.SilencingofAR,FlnAandintegrinbeta1showsthatthisternarycomplexcontrolsfocal adhesionkinase(FAK),paxillinandRac,therebydrivingcellmigration.FAK-nullfibroblastsmigratepoorlyandRacinhibition by EHT impairs motility of androgen-treated NIH3T3 cells. Interestingly, FAK and Rac activation by androgens are independentofeachother.FindingsinhumanfibrosarcomaHT1080cellsstrengthentheroleofRacinandrogensignaling. TheRacinhibitorsignificantly impairsandrogen-inducedmigrationinthese cells.AmutantAR,deletedofthesequence interacting with FlnA, fails to mediate FAK activation and