Anti-Migratory Effect of Vinflunine in Endothelial and Glioblastoma Cells Is Associated with Changes in EB1 C-Terminal DetyrosinatedTyrosinated Status.docVIP

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Anti-Migratory Effect of Vinflunine in Endothelial and Glioblastoma Cells Is Associated with Changes in EB1 C-Terminal DetyrosinatedTyrosinated Status.doc

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Anti-Migratory Effect of Vinflunine in Endothelial and Glioblastoma Cells Is Associated with Changes in EB1 C-Terminal DetyrosinatedTyrosinated Status

Anti-MigratoryEffectofVinflunineinEndothelialand GlioblastomaCellsIsAssociatedwithChangesinEB1C- TerminalDetyrosinated/TyrosinatedStatus AmandineRovini1.,Ge′raldineGauthier1,2.,Raphae¨lBerge`s1,AnnaKruczynski3,DianeBraguer1,2, Ste′phaneHonore′1,2 * 1AixMarseilleUniversite′,InstitutNationaldelaSante′ etdelaRechercheMe′dicaleUMR_S911,Marseille,France,2APHM,Ho?pitalTimone,Marseille,France,3Centrede Recherched’OncologieExpe′rimentale, InstitutdeRecherchePierreFabre,Toulouse,France Abstract Wepreviouslyshowedthatvinflunine,amicrotubule-targetingdrugoftheVinca-alkaloidfamilyexerteditsanti-angiogenic/ anti-migratory activities through an increase in microtubule dynamics and an inhibition of microtubule targeting to adhesionsites.SucheffectwasassociatedwithareductionofEB1cometlengthatmicrotubule(+)ends.Inthisworkwefirst showed that the pro-angiogenic vascular endothelial growth factor VEGF suppressed microtubule dynamics in living HumanUmbilicalVeinEndothelialCells(HUVECs),increasedEB1cometlengthby40%,andinducedEB1tobindallalong the microtubules, without modifying its expression level. Such microtubule (+) end stabilization occurred close to the plasma membrane in the vicinity of focal adhesion as shown by TIRF microscopy experiments. Vinflunine completely abolished the effect of VEGF on EB1 comets. Interestingly, we found a correlation between the reduction of EB1 comet lengthbyvinflunineandtheinhibitionofcellmigration.Byusing2Dgelelectrophoresiswedemonstratedforthefirsttime thatEB1underwentseveralpost-translationalmodificationsinendothelialandtumorcells.Particularly,theC-terminalEEY sequencewaspoorlydetectableincontrolandVEGF-treatedHUVECssuggestingtheexistenceofanon-tyrosinatedformof EB1.ByusingspecificantibodiesthatspecificallyrecognizedanddiscriminatedthenativetyrosinatedformofEB1anda putative C-terminal detyrosinated form, we showed that a detyrosinated form of EB1 exists in HUVECs and tumor cells. Interestingly, vinflunine decreasedthelevelof thedetyrosinatedfo