Abstract 923: Interrelations between roles of phospholipase C-gamma 1 inhibition, mTOR and glycolytic enzymes in growth and survival of glioblastoma cells

Glioblastoma multiforme (GBM) is a deadly and a frequently occurring brain tumor in humans. Patients with this disease survive on an average for 12-14 months after diagnosis. Conventional approaches to treat the cancer are not effective in improving patient survival. Thus, it is imperative to seek new drug targets and therapies that could effectively treat brain tumors and enhance patient survival. Phospholipase C-gamma 1 (PLCα1) plays an important role in regulating intracellular calcium stores and acts as a point of convergence in several cell signaling cascades. Inhibition of PLCα1 is known to decrease cell differentiation, invasion and motility in several cancers. We previously demonstrated inhibition of PLCα1 blocks invasion of glioma cells. In this study, we investigated the effects of PLCα1 inhibition on cell viability, cell signaling and metabolism in brain tumor (U-87 MG) cells. We investigated the hypothesis that inhibition of PLCα1 blocks cellular progression of U-87 MG. U73122, an inhibitor of PLCα1, induced a dose-related decrease in survival of U-87 MG cells, with a maximal effect at 2 µM: this finding correlated with the U73122-induced decrease in expression of lactate dehydrogenase, a protein important in U-87 MG cell survival and metabolism. Moreover, U73122 was effective in enhancing the cytotoxic potential of temozolomide, a modestly effective drug used currently for the treatment of glioblastoma. Western blot analysis of U-87 MG cells treated with U73122 at concentrations between 0.5 and 2 µM showed biphasic effects on expression of phospho-ERK and mTOR, proteins involved in PLCα1 signaling as well as hexokinase II, an important glycolytic enzyme. Employing 1H-[13C]-NMR spectroscopy, we noted that treatment with 2 µM U73122 for 72 hours induced increased glycolytic flux in U-87 MG cells. Thus, our results suggest important mechanistic interrelations between PLCα1 signaling and roles of mTOR and glycolytic enzymes in regulating survival of brain tumor cells. Furthermore, our results also suggest that inhibition of PLCα1 may be exploited in combination with conventional therapies in treating patients with glioblastoma to improve their outcome. 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 923. doi:1538-7445.AM2012-923