End-binding 1 protein overexpression correlates with glioblastoma progression and sensitizes to Vinca-alkaloids in vitro and in vivo

Raphael Berges (1) , Nathalie Baeza-Kallee (1) , Emeline Tabouret (2, 1) , Olivier Chinot (1) , Marie Petit (1, 2) , Anna Kruczynski (3) , Dominique Figarella-Branger (1) , Stephane Honore (1, 2) , Diane Braguer (1, 2)

1 CRO2 - Centre de Recherches en Oncologie biologique et Oncopharmacologie
2 TIMONE - Hôpital de la Timone [CHU - APHM]
3 Centre de Recherche en Oncologie Expérimentale

End-binding 1 protein (EB1) is a key player in the regulation of microtubule (MT) dynamics. Here, we investigated the role of EB1 in glioblastoma (GBM) tumor progression and its potential predictive role for response to Vinca-alkaloid chemotherapy. Immunohistological analysis of the 109 human GBM cases revealed that EB1 overexpression correlated with poor outcome including progression-free survival and overall survival. Downregulation of EB1 by shRNA inhibited cell migration and proliferation in vitro. Conversely, EB1 overexpression promoted them and accelerated tumor growth in orthotopically-transplanted nude mice. Furthermore, EB1 was largely overexpressed in stem-like GBM6 that display in vivo a higher tumorigenicity with a more infiltrative pattern of migration than stem-like GBM9. GBM6 showed strong and EB1-dependent migratory potential. The predictive role of EB1 in the response of GBM cells to chemotherapy was investigated. Vinflunine and vincristine increased survival of EB1-overexpressing U87 bearing mice and were more effective to inhibit cell migration and proliferation in EB1-overexpressing clones than in controls. Vinca inhibited the increase of MT growth rate and growth length induced by EB1 overexpression. Altogether, our results show that EB1 expression level has a prognostic value in GBM, and that Vinca-alkaloid chemotherapy could improve the treatment of GBM patients with EB1-overexpressing tumor.

Mots clés: RADIOTHERAPY; CHEMOTHERAPY; PLUS ENDS; glioblastoma; EB1; biomarker; Vinca-alkaloid; microtubules; MICROTUBULE-TARGETING AGENTS; BETA-CATENIN/TCF PATHWAY; PROMOTE CELLULAR GROWTH; HEPATOCELLULAR-CARCINOMA; MIGRATING CELLS; GAMMA-TUBULIN

Domaines: Cancer; Pharmacologie

Raphael Berges, Nathalie Baeza-Kallee, Emeline Tabouret, Olivier Chinot, Marie Petit, et al.. End-binding 1 protein overexpression correlates with glioblastoma progression and sensitizes to Vinca-alkaloids in vitro and in vivo. Oncotarget, 2014, 5 (24), pp.12769-12787. ⟨10.18632/oncotarget.2646⟩. ⟨hal-01310714⟩