Abstract 1394: Pro-apoptotic and anti-tumorigenic effects of a naturally occurring proteasome inhibitor on hormone-refractory prostate cancer

Abstract

Abstract A major mode by which cancer cells evade death is by an acquired ability to suppress apoptosis. In hormone refractory prostate cancer, the overexpression of pro-survival/anti-apoptotic proteins results in resistance to chemo- and radio-therapy. Hence, developing co-therapies that sensitize cells to standard treatment regimens by overcoming this apoptotic block could improve treatment outcomes in advanced prostate cancer. The naturally occurring proteasome inhibitor celastrol has been previously reported to inhibit DNA damage processing and synergize with radiotherapy to kill PC-3 cells. To further explore the mechanism by which celastrol might potentiate cell death, several lines of questioning were explored. First, the open question regarding whether or not celastrol inhibits DNA damage repair, not simply processing, was tested in the comet assay. The tail moments measured in cells treated with celastrol, irradiated and allowed to recover were significantly greater than those in untreated cells, indicating that DNA damage repair was inhibited. In other experiments, cells treated with celastrol displayed an increased expression of the pro-apoptotic, BH3 only protein Noxa. This correlated with an increase in apoptotic cell death which was further augmented by ionizing radiation treatment. The pro-survival protein NFkB is tightly controlled by IkB-alpha binding. Proteasome inhibition can suppress the pro-survival activity of NFkB by decreasing the turnover of IkB-alpha. Indeed, IkB-alpha was found to accumulate in celastrol treated cells. Further, NFkB target gene activation was markedly reduced. To test the feasibility of celastrol treatment in animals, the PC-3 xenograft model in the athymic nude mouse was employed. When celastrol was combined with radiotherapy, tumor volume decreased, apoptosis increased, angiogenesis decreased, and NFkB target gene mRNA levels were found to be lower. Taken together, these data show that celastrol sensitized PC-3 cells to radiation both in vitro and in vivo by impairing DNA damage repair and augmenting apoptosis through suppressing NFkB activation and increasing the protein levels of Noxa. Celastrol may hold promise as a co-therapy with radiation for the treatment of hormone-refractory prostate cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1394.