Abstract A159: The Redox/ Fyn/c-Cbl pathway and its interaction with Cool-1: A novel pathway that regulates chemosensitivity in glioblastoma

Abstract

Abstract GBMs are the most common primary brain tumor, accounting for 52 percent of all diagnosed brain tumors. It is also the most devastating of all brain tumors, with a five-year survival rate of 3.3 percent. One of the reasons for this poor prognosis is resistance of tumor cells to treatment with chemotherapy. We have discovered a novel means by which GBMs become chemoresistant, based on inhibition of the redox/Fyn/c-Cbl pathway by overexpression of Cool-1. The protein c-Cbl, a receptor tyrosine kinase adaptor protein, is responsible for the ubiquitination and degradation of epidermal growth factor receptor (EGFR) and other receptor protein kinases critical in cell division and cell survival. c-Cbl is activated by Fyn kinase, which itself can be activated by agents that make cells more oxidized. In normal glia and glial progenitor cells of the CNS, exposure to chemotherapy makes cells more oxidized, leading to sequential activation of Fyn and c-Cbl. In GBMs, in contrast, exposure of GBM cells to BCNU or to chemical pro-oxidants does not lead to c-Cbl activation. Further studies demonstrated that these agents did cause Fyn activation, suggesting that GBMs inhibit Fyn-mediated c-Cbl activation. This would lead to decreased degradation of EGFR, thus enabling continued cell division and providing resistance to chemotherapy. We therefore set out to test the hypothesis that reversal of this inhibition would decrease cell division and enhance susceptibility to chemotherapy-induced cell death. In this work we discovered that oxidant-associated c-Cbl activation can be restored by suppressing expression of the protein Cool-1, which is over-expressed in many cancers including GBM. Our data further demonstrates that Cool-1 and Cbl interact, that genetic reduction in Cool-1 levels by expression of small inhibitory RNAs restores normal c-Cbl-mediated degradation of RTKs (including EGFR) in response to exposure to pro-oxidants and BCNU, and that restoration of normal c-Cbl activation also increases sensitivity to this and other chemotherapeutic agents. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A159.