Abstract 1841: A miR551b/catalase/MUC1/EGFR cascade for acquired apoptosis resistance and chemoresistance in lung cancer cells

Abstract

Abstract The oncoprotein Mucin-1 (MUC1) plays multiple roles in the development of different human tumors. However, whether MUC1 is involved in acquired chemoresistance, a major challenge in cancer therapy, has not been determined. Using a lung cancer cell model with acquired apoptosis resistance (AR)-associated chemoresistance, we investigated the role and mechanism of MUC1 in acquired chemoresistance. MUC1 expression was substantially increased in cells with acquired apoptosis resistance and knockdown of MUC1 expression effectively increased sensitivity of the AR cells to apoptotic cytotoxicity induced by anticancer therapeutics, substantiating a role for MUC1 in acquired chemoresistance. Decreased hydrogen peroxide-reducing enzyme catalase and increased cellular reactive oxygen species (ROS) were found to be associated with MUC1 overexpression. Pharmacological ROS scavengers or exogenous catalase dramatically suppressed MUC1 expression, suggesting catalase suppression-mediated ROS accumulation contributes to MUC1 overexpression. Further, we found miR-551b expression was increased in the AR cells. Knockdown of miR-551b restored catalase expression, and suppressed ROS accumulation and MUC1 expression. Finally, with manipulation of MUC1 expression, we found MUC1 promotes EGFR-mediated activation of the cell survival Akt/c-FLIP/Cox2/Mcl-1 cascade and stabilization of anti-apoptosis factors c-IAP1 and c-IAP2. Thus, our results establish a role for MUC1 in acquired chemoresistance and a pathway consisting of miR-551b/catalase/ROS for MUC1overexpression, and interventions against this pathway may be exploited for overcoming acquired chemoresistance. Citation Format: Xiuling Xu, Alexandria Wells, Mabel T. Padilla, Kwang Chul Kim, Yong Lin. A miR551b/catalase/MUC1/EGFR cascade for acquired apoptosis resistance and chemoresistance in lung cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1841. doi:10.1158/1538-7445.AM2014-1841