Abstract 242: Anti-obesity drugorlistat enhances sensitivity toTRAIL by two different pathways inhormone-refractory prostate cancer cells

Abstract

Abstract Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is considered as one of the expected cancer therapeutics. However, since hormone-refractory prostate cancer (HRPC) cells are sometimes resistant to TRAIL, we need to develop a novel strategy to overcome. We demonstrated that the anti-obesity drug orlistat enhances the sensitivity to TRAIL in HRPC cells. The combination of orlistat and TRAIL remarkably induced apoptosis in DU145 and PC3 cells. Orlistat induced the expression of DR5, which is one of the TRAIL receptors. The suppression of DR5 with siRNA reduced the enhanced apoptosis, suggesting that the enhanced apoptosis was at least partially due to the up-regulation of DR5. Although the up-regulation of DR5 at both mRNA and protein levels by orlistat was observed in both cell lines, the activation of the DR5 promoter in DU145 cells was CHOP-dependent, but that in PC3 cells was CHOP-independent. Moreover, orlistat induced reactive oxygen species (ROS), and a ROS scavenger diminished the sensitivity to TRAIL through the suppression of the CHOP and DR5 expressions in both cell lines. These results suggest that there are two different pathways of up-regulation of DR5 by orlistat, which are ROS-CHOP pathway and ROS-direct pathway. In conclusion, orlistat enhances the sensitivity to TRAIL in the ROS mediated pathways in prostate cancer cells. We believe that the administration of TRAIL and orlistat is considered a promising strategy for cancer therapy in HRPC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 242. doi:1538-7445.AM2012-242