Abstract 2791: Disruption of EB1 comets from microtubule “plus” ends and induction of microtubule catastrophes are intrinsic mechanisms of patupilone-induced inhibition of glioblastoma cell migration

Abstract

Abstract Glioblastoma are the most frequent primary tumors of central nervous system. They are very aggressive, highly angiogenic and associated with very bad prognostic. One of the main biological features of a glioblastoma is the local invasion of its constituent neoplastic cells into the surrounding brain tissue. This invasive behavior represents a major obstacle to an effective treatment of intrinsic brain tumors. Therefore, it seems very important to target glioblastoma cell migration. Although many of the genetic alterations that deregulate the cell processes of growth and death, and are involved in tumor initiation have been elucidated in recent years, less progress has been done to understand the complex processes of migration. As a consequence, no specific therapeutic strategy against tumor cell migration is currently used to manage glioblastoma invasion. The Epothilones are a new class of microtubule (MT) stabilizing agents, which exert their cytotoxic activity by suppressing microtubule dynamics and that have strong anti-cancer activity both in vitro and in vivo. This drug family is active against cancer cells resistant to paclitaxel or to cells developing resistance to taxanes. Among the Epothilones, Patupilone (Epothilone B, EPO 906) is able to cross the blood-brain barrier since its activity is fully P-gp independent. Moreover, patupilone specifically targets αIII-tubulin, which is over expressed in glioblastomas. Here, we investigated the anti-migratory potential of patupilone through its effects on MT dynamics in glioblastoma cells. At non-cytotoxic concentrations, Patupilone inhibited glioblastoma cell migration, as shown by transwell cell migration, random motility and spheroids assay. This was associated with EB1 and related MT “plus” end tracking proteins comet shortening; and with MT catastrophes induction, without modification of any other MT dynamic instability parameters, including the microtubule growth rate. Such effect on MT catastrophes led to the disruption of MT stabilization at the leading edge. Evaluation of the effect of patupilone on EB comets and MT dynamics in a reconstituted in vitro system revealed that MT stabilizing drugs intrinsically induce MT catastrophes and disrupt EB comets at MT “plus” end. We have demonstrated that patupilone antagonizes glioblastoma cell migration by a new mechanism i.e. disruption of EB1 comets and induction of MT catastrophes distinct from its cytotoxic main mechanism i.e suppression of microtubule dynamic instability. Altogether, our results suggest that EB proteins may represent new potential target for anti-cancer therapy in highly invasive tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2791. doi:1538-7445.AM2012-2791