Inositol hexakisphosphate kinase 2 sensitizes ovarian carcinoma cells to multiple cancer therapeutics

We recently identified inositol hexakisphosphate kinase 2 (IP6K2) as a positive regulator of apoptosis. Overexpression of IP6K2 enhances apoptosis induced by interferon- beta (IFN- beta ) and cytotoxic agents in NIH-OVCAR-3 ovarian carcinoma cells. In this study, we contrast and compare IFN- beta and radiation-induced death, and show that IP6K2 expression sensitizes tumor cells. Unirradiated NIH-OVCAR-3 cells transfected with IP6K2 formed fewer colonies compared to unirradiated vector-expressing cells. IP6K2 overexpression caused increased radiosensitivity, evidenced by decreased colony forming units (CFU). Both IFN- beta and radiation induced caspase 8. IFN- beta , but not gamma -irradiation, induced TRAIL in NIH-OVCAR-3 cells. Gamma irradiation, but not IFN- beta , induced DR4 mRNA. Apoptotic effects of IFN- beta or gamma -irradiation were blocked by expression of a dominant negative mutant death receptor 5 (DR5 Delta ) or by Bcl-2. Caspase-8 mRNA induction was more pronounced in IP6K2-expressing cells compared to vector-expressing cells. These data suggest that overexpression of IP6K2 enhances sensitivity of some ovarian carcinomas to radiation and IFN- beta . IP6K2 may function to enhance the expression and/or function of caspase 8 and DR4 following cell injury. Both IFN- beta and gamma -irradiation induce apoptosis through the extrinsic, receptor-mediated pathway, IFN- beta through TRAIL, radiation through DR4, and both through caspase 8. The function of both death inducers is positively regulated by IP6K2.