Abstract
Abstract Sensitization of cancer cells to tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), particularly TRAIL-resistant cancer cells, could improve the effectiveness of TRAIL as a potential chemotherapy drug. Therefore, development of safe novel pharmacological agents that could sensitize the tumor cells to TRAIL should be an effective strategy to kill the chemotherapy resistance cancer cells. We have recently shown that inhibition of polyol pathway enzyme, aldose reductase (AR) that mediates NF-kB-dependent expression of inflammatory markers, prevents human colon cancer cell growth and metastasis in culture as well in nude mouse models. We now have investigated the role of AR in sensitizing cancer cells to TRAIL and potentiating TRAIL-induced apoptosis of human colon cancer cells. Our results demonstrate that inhibition of AR potentiates TRAIL-induced apoptosis in colon cancer cells (HT-29, HCT-116) by upregulation of both death receptor (DR)-5 and DR4. Specific siRNAs -mediated knockdown of DR5 and DR4 significantly (>85%) reduced the sensitizing effect of AR inhibition by pharmacological agent, fidarestat, on TRAIL-induced apoptosis. AR inhibition also down-regulated TRAIL-induced cell survival proteins such as Bcl-xL, Bcl-2, survivin, XIAP, and cFLIP, and up-regulated the expression of pro-apoptotic proteins such as Bax. Further, AR inhibition also altered the mitochondrial membrane potential leading to cytochrome c release, caspases-3 activation and PARP cleavage. Furthermore, our results indicate that AR inhibition regulates AKT/PI3K-dependent activation of forkhead transcription factor FOXO3a. Knockdown of FOXO3a significantly (>80%) abolished AR inhibition-induced upregulation of DR5 and DR4 and apoptosis in colon cancer cells. Overall, our results show that AR inhibition potentiates TRAIL-induced apoptosis through down-regulation of cell survival proteins and upregulation of death receptors and thus AR inhibitors along with TRAIL could be effective therapy for the treatment of colon cancer. 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 247. doi:1538-7445.AM2012-247
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