This Article Full Text Full Text (PDF) Suplementary Material Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Honoré, S. Articles by Braguer, D. PubMed PubMed Citation Articles by Honoré, S. Articles by Braguer, D.

Research Articles: Therapeutics, Targets, and Development

Antiangiogenic vinflunine affects EB1 localization and microtubule targeting to adhesion sites

¹ 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; and ² Pierre Fabre Oncology Research Institute, Toulouse, France

Requests for reprints: Diane Braguer, UFR Pharmacie, Institut National de la Sante et de la Recherche Medicale UMR 911, 27 Boulevard Jean Moulin, 13005 Marseilles, France. Phone: 33-4918-35635; Fax: 33-4918-35635. E-mail: diane.braguer{at}univmed.fr

Abstract

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. [Mol Cancer Ther 2008;7(7):2080–9]

Grant support: INCa and Cancéropole PACA (RS019), and by European Commission FP6 specific targeted project Nano4drugs (LSHB-CT-2005-019102).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

³ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 2/12/08; revised 4/ 7/08; accepted 4/23/08.