Establishment and Validation of Computational Model for MT1-MMP Dependent ECM Degradation and Intervention Strategies 英文参考文献.docVIP

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Establishment and Validation of Computational Model for MT1-MMP Dependent ECM Degradation and Intervention Strategies 英文参考文献.doc

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Establishment and Validation of Computational Model for MT1-MMP Dependent ECM Degradation and Intervention Strategies 英文参考文献

EstablishmentandValidationofComputationalModel forMT1-MMPDependentECMDegradationand InterventionStrategies DaisukeHoshino1,NaohikoKoshikawa1,TakashiSuzuki2,3,VitoQuaranta4,AlissaM.Weaver4, MotoharuSeiki1,3*,KazuhisaIchikawa3,5 1Division of Cancer CellResearch,Institute ofMedical Science, University ofTokyo, Minato-ku, Tokyo, Japan, 2Division of Mathematical Science,Graduate School of EngineeringScience,OsakaUniversity,Toyonaka,Osaka,Japan,3JST,CREST,Chiyoda-ku,Tokyo,Japan,4DepartmentofCancerBiology,VanderbiltUniversityMedical Center,Nashville,Tennessee,UnitedStatesofAmerica,5DivisionofMathematicalOncology,InstituteofMedicalScience,UniversityofTokyo,Minato-ku,Tokyo,Japan Abstract MT1-MMP is a potent invasion-promoting membrane protease employed by aggressive cancer cells. MT1-MMP localizes preferentiallyatmembraneprotrusionscalledinvadopodiawhereitplaysacentralroleindegradationofthesurrounding extracellular matrix (ECM). Previous reports suggested a role for a continuous supply of MT1-MMP in ECM degradation. However, the turnover rate of MT1-MMP and the extent to which the turnover contributes to the ECM degradation at invadopodia have not been clarified. To approach this problem, we first performed FRAP (Fluorescence Recovery after Photobleaching)experimentswithfluorescence-taggedMT1-MMPfocusingonasingleinvadopodiumandfoundveryrapid recoveryinFRAPsignals,approximatedbydouble-exponentialplotswithtimeconstantsof26sand259s.Therecovery dependedprimarilyonvesicletransport,butnegligiblyonlateraldiffusion.Nextweconstructedacomputationalmodel employingtheobservedkineticsoftheFRAPexperiments.ThesimulationssuccessfullyreproducedourFRAPexperiments. Nextweinhibitedthevesicletransportbothexperimentally,andinsimulation.Additionofdrugsinhibitingvesicletransport blockedECMdegradationexperimentally,andthesimulationshowednoappreciableECMdegradationunderconditions inhibitingvesicletransport.Inaddition,thedegreeofthereductioninECMdegradationdependedonthedegreeofthe reductionintheMT1-