Epothilone B inhibits migration of glioblastoma cells by inducing microtubule catastrophes and affecting EB1 accumulation at microtubule plus ends.
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.
INSERM UMR 911, Centre de Recherche en Oncologie Biologique et en Oncopharmacologie, Aix-Marseille Université, 27 Boulevard Jean Moulin, 13385 Marseille Cedex 5, France. alessandra.pagano@univ-amu.fr
Alessandra
A
Pagano
Stéphane
S
Honoré
Renu
R
Mohan
Raphael
R
Berges
Anna
A
Akhmanova
Diane
D
Braguer
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D034261:Epothilones / Q000494:pharmacology*; D005909:Glioblastoma / Q000473:pathology*; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D050257:Tubulin Modulators / Q000494:pharmacology*
D000970:Antineoplastic Agents; D034261:Epothilones; C500985:MAPRE1 protein, human; D008869:Microtubule-Associated Proteins; D050257:Tubulin Modulators; C093788:epothilone B