Effects of interferons and double-stranded RNA on human prostate cancer cell apoptosis

Prostate cancer is the second most commonly diagnosed cancer among men in the United States. Prostate cancer therapy is severely hampered by lack of response and development of resistance to conventional chemotherapeutic drugs in patients. Therefore, the development and discovery of new drugs have become an urgent clinical need. Interferons (IFNs), a family of pleiotropic cytokines, exert antitumor activities due to their anti-proliferative, immunomodulatory and proapoptotic functions. Here, we report that pretreatment of prostate cancer PC-3 cells with IFNs sensitized these cells to double-stranded RNAs (dsRNAs)-induced apoptosis. The enhancement effect of IFN treatment was dependent on IFN subtypes, in particular, IFN gamma. In comparison with IFN alpha or beta, IFN gamma treatment remarkably augmented apoptosis in PC-3 cells induced with polyinosinic: polycytidylic acid (poly I: C), a synthesized form of dsRNA. We demonstrated that IFN-signaling was necessary for these effects by using mutant cell lines. Transfection of 2-5A, the activator of RNase L, or silencing of dsRNA-dependent protein kinase R (PKR) by siRNA did not have any significant impact on this event, suggesting that neither RNase L nor PKR was involved in poly I: C/IFN gamma-induced apoptosis in the cells. Further investigation of the apoptotic pathway revealed that Bak, a pro-apoptotic member of the Bcl-2family, was synergistically up-regulated by IFN gamma and poly I: C, whereas other members of the family were not affected. Knocking down of Bak demonstrated its contribution to poly I: C/IFN gamma-induced apoptosis in the cells. We believeour findings will precipitate the design of novel therapeutic strategies for prostate cancer.