Silymarin Targets β-Catenin Signaling in Blocking MigrationInvasion of Human Melanoma Cells 英文参考文献.docVIP

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Silymarin Targets β-Catenin Signaling in Blocking MigrationInvasion of Human Melanoma Cells 英文参考文献.doc

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Silymarin Targets β-Catenin Signaling in Blocking MigrationInvasion of Human Melanoma Cells 英文参考文献

SilymarinTargetsb-CateninSignalinginBlocking Migration/InvasionofHumanMelanomaCells MuditVaid1,RamPrasad1,QianSun1,SantoshK.Katiyar1,2,3* 1Department ofDermatology, University ofAlabama atBirmingham,Birmingham,Alabama, United States ofAmerica, 2ComprehensiveCancer Center, University of AlabamaatBirmingham,Birmingham,Alabama,UnitedStatesofAmerica,3BirminghamVAMedicalCenter,Birmingham,Alabama,UnitedStatesofAmerica Abstract Metastaticmelanomaisaleadingcauseofdeathfromskindiseases,andisoftenassociatedwithactivationofWnt/b-catenin signalingpathway.Wehaveexaminedtheinhibitoryeffectofsilymarin,aplantflavanoidfromSilybummarianum,oncell migration of metastasis-specific human melanoma cell lines (A375 and Hs294t) and assessed whether Wnt/b-catenin signalingisthetargetofsilymarin.Usinganinvitroinvasionassay,wefoundthattreatmentofhumanmelanomacelllines withsilymarinresultedinconcentration-dependentinhibitionofcellmigration,whichwasassociatedwithaccumulationof cytosolic b-catenin, while reducing the nuclear accumulation of b-catenin (i.e., b-catenin inactivation) and reducing the levels of matrix metalloproteinase (MMP) -2 and MMP-9 which are the down-stream targets of b-catenin. Silymarin enhanced:(i)thelevelsofcaseinkinase1a,glycogensynthasekinase-3bandphosphorylated-b-cateninoncriticalresidues Ser45,Ser33/37 andThr41,and(ii)thebindingofb-transducinrepeat-containingproteins(b-TrCP)withphosphoformsofb- catenininmelanomacells.Theseeventsplayimportantrolesindegradationorinactivationofb-catenin.Toverifywhether b-cateninisapotentmoleculartargetofsilymarin,theeffectofsilymarinwasdeterminedonb-catenin-activated(Mel1241) andb-catenin-inactivated(Mel1011)melanomacells.TreatmentofMel1241cellswithsilymarinorFH535,aninhibitorof Wnt/b-catenin pathway, significantly inhibited cell migration of Mel 1241 cells, which was associated with the elevated levelsofcaseinkinase1aandglycogensynthasekinase-3b,anddecreasedaccumulationofnuclearb-cateninandinhibition ofMMP-2andMMP-9levels.However,thise