MVL-PLA2, a Snake Venom Phospholipase A2, Inhibits Angiogenesis through an Increase in Microtubule Dynamics and Disorganization of Focal Adhesions 英文参考文献.docVIP

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MVL-PLA2, a Snake Venom Phospholipase A2, Inhibits Angiogenesis through an Increase in Microtubule Dynamics and Disorganization of Focal Adhesions 英文参考文献.doc

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MVL-PLA2, a Snake Venom Phospholipase A2, Inhibits Angiogenesis through an Increase in Microtubule Dynamics and Disorganization of Focal Adhesions 英文参考文献

MVL-PLA2,aSnakeVenomPhospholipaseA2,Inhibits AngiogenesisthroughanIncreaseinMicrotubule DynamicsandDisorganizationofFocalAdhesions AmineBazaa1,EddyPasquier2¤,Ce′lineDefilles2,InesLimam1,RaoudhaKessentini-Zouari1,OlfaKallech- Ziri1,AssouElBattari2,DianeBraguer2,MohamedElAyeb1,NazihaMarrakchi1,3,Jose′ Luis2* 1LaboratoiredesVeninsetToxines,InstitutPasteurdeTunis,Tunis,Tunisia,2INSERMUMR911,CRO2,Aix-MarseilleUniversite′,Marseille,France,3Faculte′ deMe′decine deTunis,Tunis,Tunisia Abstract Integrinsareessentialprotagonistsofthecomplexmulti-stepprocessofangiogenesisthathasnowbecomeamajortarget forthedevelopmentofanticancertherapies.WerecentlyreportedandcharacterizedthatMVL-PLA2,anovelphospholipase A2fromMacroviperalebetinavenom,exhibitedanti-integrinactivity.Inthisstudy,weshowthatMVL-PLA2alsodisplays potent anti-angiogenic properties. This phospholipase A2 inhibited adhesion and migration of human microvascular- endothelialcells(HMEC-1)inadose-dependentmannerwithoutbeingcytotoxic.UsingMatrigelTMandchickchorioallantoic membrane assays, we demonstrated that MVL-PLA2, as well as its catalytically inactivated form, significantly inhibited angiogenesisbothinvitroandinvivo.Wehavealsofoundthattheactincytoskeletonandthedistributionofavb 3integrin, acriticalregulatorofangiogenesisandamajorcomponentoffocaladhesions,weredisturbedafterMVL-PLA2treatment.In ordertofurtherinvestigatethemechanismofactionofthisproteinonendothelialcells,weanalyzedthedynamicinstability behavior of microtubules in living endothelial cells. Interestingly, we showed that MVL-PLA2 significantly increased microtubuledynamicityinHMEC-1cellsby40%.Weproposethattheenhancementofmicrotubuledynamicsmayexplain thealterationsintheformationoffocaladhesions,leadingtoinhibitionofcelladhesionandmigration. Citation:BazaaA,PasquierE,DefillesC,LimamI,Kessentini-ZouariR,etal.(2010)MVL-PLA2,aSnakeVenomPhospholipaseA2,InhibitsAngiogenesisthroughan IncreaseinMicrotubuleDynamicsandDisorganizationofFocalAdhesions.PL