Apoptosis Induction by Targeting Interferon Gamma Receptor 2 (IFNgammaR2) in Prostate Cancer: Ligand (IFNgamma)-Independent Novel Function of IFNgammaR2 as a Bax Inhibitor

Abstract

Abstract : In our preliminary study, we found that IFN(gamma)R2 has previously unknown function as an inhibitor of Bax. Bax is a key mediator of apoptosis. We found that IFN(gamma) R2 is overexpressed in prostate cancer, and we hypothesize that abnormally high level of IFN(gamma)R2 confers apoptosis resistance of prostate cancer. In this project, we will investigate the role of IFN(gamma)R2 in drug resistance of prostate cancer and explore the development of therapeutic peptide that can activate Bax-induced apoptosis in prostate cancer by inactivating IFN(gamma)R2. In Year 2, we planned to determine the presence of subtype of prostate cancer expressing high levels of IFN(gamma)R2 and Bax which is expected to be an ideal target subtype treated by IFN(gamma)R2 inhibiting strategy. We also planned to determine the effectiveness of IFN(gamma)R2 inhibition both in mouse model and cell culture model. We obtained results showing that (1) majority of prostate cancer tissue showed increased expression of IFN(gamma)R2 in comparison with normal prostate tissue, and that (2) IFN(gamma)R2 knockdown suppressed tumor growth (human cancer cells were transplanted to mouse) in nude mouse, and (3) parthenolide, a plant-derived compound, was able to decrease IFN(gamma)R2 expression in prostate cancer cells and induced cell death. We will continue our investigation to determine the mechanism of IFN(gamma)R2 overexpression in prostate cancer, and to develop technologies to induce prostate cancer cell death by targeting IFN(gamma)R2.