Journal
BIOCHEMICAL PHARMACOLOGY
Volume 84, Issue 4, Pages 432-443Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2012.05.010
Keywords
Microtubule; EB proteins; Glioblastoma; Cell migration; Epothilone B
Categories
Funding
- Canceropole PACA
- INCa [RS019]
- EMBO Long Term Fellowship
- Marie-Curie fellowship
- Netherlands Organization for Scientific Research (NOW) ALW VICI
- FUI Provence-Alpes Cote d'Azur council
- Conseil General 13
- Association pour la Recherche sur les Tumeurs Cerebrales (ARTC)
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Invasion of normal brain tissue by tumor cells is a major contributing factor to the recurrence of glioblastoma and its resistance to therapy. Here, we have assessed the efficacy of the microtubule (MT) targeting agent Epothilone B (patupilone) on glioblastoma cell migration, a prerequisite for invasive tumor cell behavior. At non-cytotoxic concentrations, patupilone inhibited glioblastoma cell movement, as shown by transwell cell migration, random motility and spheroid assays. This anti-migratory effect was associated with a reduced accumulation of EB1 and other MT plus end tracking proteins at MT ends and with the induction of MT catastrophes, while the MT growth rate and other MT dynamic instability parameters remained unaltered. An increase in MT catastrophes led to the reduction of the number of MTs reaching the leading edge. Analysis of the effect of patupilone on MT dynamics in a reconstituted in vitro system demonstrated that the induction of MT catastrophes and an alteration of EB1 accumulation at MT plus end are intrinsic properties of patupilone activity. We have thus demonstrated that patupilone antagonizes glioblastoma cell migration by a novel mechanism, which is distinct from suppression of MT dynamic instability. Taken together, our results suggest that EB proteins may represent a new potential target for anti-cancer therapy in highly invasive tumors. (C) 2012 Elsevier Inc. All rights reserved.
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