Grant: Operating Grant

Inositol phosphates (IPs) are signaling molecules that regulate many cellular functions. Over the past 2 decades, evidence has accumulated demonstrating IP profiles of cancer cells are distinct from profiles of normal cells and alterations of cellular IP profiles can beneficially impact the cancer phenotype. With clear and growing evidence that the IP profile of cells change with cell proliferation and modulation of this profile can control proliferation of cancer cells, we ask the question: What is the best way to target IP signaling to utilize these anti-cancer effects? Previous studies have revealed modulation of IP signaling promotes apoptosis and increases the effectiveness of anti-cancer drugs in numerous cultured cell and animal cancer models. These studies have concentrated on IP6 as a pro-apoptotic signal and potential anti-cancer therapeutic. However, there is no strong evidence identifying IP6 as the direct, active agent. In fact, this idea is refuted by reports that over-production of IP6 in cells lead to the inhibition of apoptosis. Clearly, the model of IP6 as a pro-apoptotic signal must be reevaluated. To explore new approaches to modulate IP profiles and promote apoptosis, we hypothesize actions of IP kinases, which comprise the IP6-synthetic pathway, counteract pro-apoptosis signaling, and by inhibiting these kinases we can promote apoptosis and mimic the pro-apoptotic actions of IP6. Currently, there are no chemicals available to inhibit IP kinases and explore their roles cancer cells. We propose to overcome this obstacle by engineering IP kinases, such that we can control their actions using chemicals. This will provide valuable and novel insight into the IP signaling pathway and the roles of IP kinases in cancer. Further, using this approach we can evaluate IP kinase inhibition as a route to sensitizing cells to apoptosis-inducing agents and increasing the efficacy of current anti-cancer therapeutics.