Cellular senescence is a tumor suppressor mechanism. However glioblastoma multiforme (GBM), the most malignant primary brain tumor with a median survival of about one year, is highly resistant to senescence. There is a critical need for new therapeutic modalities and agents that sensitize GBM to senescence to improve patient outcome. A family of PI5P4K phosphorylates phosphatidylinositol 5-phosphate (PI5P) and converts it to phosphatidylinositol 4,5-phosphate (PI[4,5]P2) to regulate phosphoinositide signaling. In the preliminary studies, my laboratory found that PI5P4K? binds directly to guanine nucleotides. Our X-ray structural analyses show that PI5P4K? utilizes GTP as the preferred phospho-donor, as opposed to ATP. Kinetic analyses also predict that physiological GTP levels control the PI5P4K? activity. Importantly, we have found that cellular GTP levels play critical rol in suppressing GBM senescence and that PI5P4K? knockdown triggers senescence of GBM cells. We have identified a small chemical compound that inhibits PI5P4K activity in vitro and in vivo. The treatment of the PI5P4K chemical inhibitor induces senescence of GBM cells. These results indicate that inhibitors of PI5P4K? could be useful in preventing or treating GBM. The goal of this proposal is to determine the significance of a novel type of GTP-dependent kinase, PI5P4K?, in regulating GBM senescence, and to determine whether inhibition of PI5P4? could induce GBM senescence and reduce its tumorigenic activity in vitro and in vivo. To test the hypothesis, we will determine the role of PI5P4K? in GBM cell growth by shRNA-mediated PI5P4K? knockdown and pharmacological inhibition using in vitro cell culture and a clinically relevant orthotopic implantation model of glioblastoma (Aim 1). We will use biochemical and biological analyses to determine the mechanism of GTP detection by PI5P4K? (Aim 2). We will determine how PI5P4K? regulates senescence by characterizing PI5P4K? downstream effectors (Aim 3). Collectively, these studies will lead to reveal the novel mechanism and opportunity for inducing senescence and growth arrest of glioblastoma cells by targeting PI5P4K?.
Glioblastoma multiforme (GBM) is the most prominent and malignant primary brain tumor confers a dismal median survival of about one year. In this proposal we will test the hypothesis that inhibition of PI5P4K (phosphatidylinositol-5-phosphate 4-kinase-)will serve as a new therapeutic strategy against GBM. We will use pharmacological and molecular approaches that target PI5P4K in GBM cell culture and in GBM animal tumor models.
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