Abstract 3824: Targeting MUC1-C oncoprotein inhibits AKT-S6K1-elF4A pathway regulated TIGAR translation in colorectal cancer

Abstract

Abstract Colorectal cancer is third most common malignancy and is the second most common cause of cancer-related death. The MUC1 multi-domain oncoprotein is aberrantly overexpressed in colorectal cancer and has been linked to poor outcomes in this disease. However, it is not known if MUC1 is of functional significance to colorectal tumors. Here, we investigate the effects of the MUC1-C inhibitor (GO-203), which disrupts MUC1-C homo-oligomerization, on AKT-mTORC-S6K translation pathway in human colorectal cancer cells. The present study demonstrates that GO-203 treatment was associated with inhibition of AKT-S6K1 signaling in colorectal cancer cells. Targeting MUC1-C with GO-203 downregulates TP53-inducible glycolysis and apoptosis regulator (TIGAR) protein. We show that GO-203-induced suppression of TIGAR is mediated by inhibition of AKT and the downstream mTOR pathway. The results also demonstrate that targeting MUC1-C blocks eIF4A cap-dependent translation of TIGAR. TIGAR promotes the shunting of glycolytic intermediates into the pentose phosphate pathway and thus is of importance for maintaining redox balance. In concert with these results, GO-203-induced suppression of TIGAR was associated with decreases glutathione levels. GO-203 treatment also resulted increases in reactive oxygen species (ROS) and loss of mitochondrial transmembrane potential. Consistent with these results, GO-203 inhibited the growth of colon cancer cells in vitro and xenografts in nude mice. These findings thus indicate that MUC1-C is a potential target for the treatment of colorectal cancer. Citation Format: Rehan Ahmad, Maroof Alam, Omar Al-Obaid, Masanori Hasegawa, Donald Kufe. Targeting MUC1-C oncoprotein inhibits AKT-S6K1-elF4A pathway regulated TIGAR translation in colorectal cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3824.