End-binding 1 protein overexpression correlates with glioblastoma progression and sensitizes to Vinca-alkaloids in vitro and in vivo
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Raphael Berges1, Nathalie Baeza-Kallee1, Emeline Tabouret1,2, Olivier Chinot1,2, Marie Petit1,2, Anna Kruczynski3, Dominique Figarella-Branger1,2, Stephane Honore1,2, Diane Braguer1,2
1Aix-Marseille Université, INSERM, CRO2 UMR_S 911, Marseille 13385, France
2APHM, CHU Timone, Marseille 13385, France
3Centre de Recherche d'Oncologie Expérimentale, Institut de Recherche Pierre Fabre, Toulouse, France
Diane Braguer, e-mail: [email protected]
Keywords: glioblastoma, EB1, biomarker, Vinca-alkaloid, microtubules
Received: July 03, 2014 Accepted: October 26, 2014 Published: November 28, 2014
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.
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