CBIO-44RESTING MEMBRANE POTENTIAL CONTROLS STEM CELL STATE AND DIFFERENTIATION OF GLIOBLASTOMA CANCER STEM CELLS

Abstract

Glioblastoma (GBM) is the most common malignant brain tumor in adults with a poor prognosis despite aggressive treatment. Resting membrane potential (RMP) has been shown to be an important signaling mechanism in physiological stem cells. Further the importance of ion channels and RMP have been studied in glioma. We evaluated the relevance of RMP in GBM in the context of the cancer stem cell(CSC) hypothesis. Undifferentiated GBM CSCs were depolarized compared to differentiated counterparts [RMP of -5 +/- 4 (n = 33) -24 + /- 20 (n = 31, P < 0.001)]. Depolarization using exogenous potassium (KCl) of GBM CSCs grown under differentiating conditions was sufficient to prevent differentiation and enhance self renewal when compared to osmotic controls (NaCl). Hyperpolarization using genetic (mutant TREK transduction) and pharmacological (omeprazole and salinomycin) was sufficient to induce differentiation and limit self renewal in GBM CSCs grown under undifferentiated conditions. To evaluate for a mechanism mediating this phenomenon we performed a phospho-protein array comparing the undifferentiated GBM CSCs and those treated with omeprazole or salinomycin. We noted upregulation of phospho-proteins related to senescence pathways in treated cells but no specific key pathway. Finally, this evidence suggests that RMP may be an important regulator of stem cell state of GBM CSCs. Further it may be a target of novel treatment strategies.