Antiangiogenic vinflunine affects EB1 localization and microtubule targeting to adhesion sites.
The motile behavior of endothelial cells is a crucial event for neoangiogenesis. We previously showed that noncytotoxic concentrations of vinflunine inhibit capillary-like tube formation on Matrigel and endothelial cell migration with a concomitant increase in interphase microtubule dynamic instability. In this article, we further investigated the effects of vinflunine on migration and cytoskeleton interaction dynamics in HMEC-1 endothelial cells. We confirmed that vinflunine, at low and noncytotoxic concentrations (0.01-1 nmol/L), inhibited endothelial cell random motility by 54%. This effect was associated with a decrease in the percentage of stable microtubules and in the mean duration of pauses for dynamic ones. Moreover, we found that vinflunine altered adhesion site targeting by microtubules and suppressed the microtubule (+) end pause that occurs at adhesion sites during cell migration (from 151 +/- 20 seconds in control cells to 38 +/- 7 seconds in vinflunine-treated cells, P < 0.001). This effect was associated with the inhibition of adhesion site dynamics and the formation of long-lived stress fibers. Importantly, we found that vinflunine altered EB1 localization at microtubule (+) ends. These results highlight a new mechanism of action of vinflunine, which act by disrupting the mutual control between microtubule and adhesion site dynamics and strengthen the role of +TIPs proteins such as EB1 as key regulators of endothelial cell motility.
Honoré
Stéphane
S
Institut National de la Sante et de la Recherche Medicale UMR 911, Centre de Recherche en Oncologie Biologique et en Oncopharmacologie Aix-Marseille Université, Marseilles, France.
Pagano
Alessandra
A
Gauthier
Géraldine
G
Bourgarel-Rey
Véronique
V
Verdier-Pinard
Pascal
P
Civiletti
Karine
K
Kruczynski
Anna
A
Braguer
Diane
D
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D016764:Cell Polarity / Q000187:drug effects; D042783:Endothelial Cells / Q000166:cytology* / Q000187:drug effects*; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D022502:Stress Fibers / Q000187:drug effects; D014747:Vinblastine / Q000031:analogs & derivatives* / Q000494:pharmacology
D020533:Angiogenesis Inhibitors; C405804:EB1 microtubule binding proteins; D008869:Microtubule-Associated Proteins; C111217:vinflunine; D014747:Vinblastine