Abstract 3564: MUC13 protects colorectal cancer cells from death by activating the NF-κb pathway and is a potential therapeutic target

Abstract

Abstract MUC13 is a transmembrane mucin glycoprotein that is overexpressed by many cancers, although its functions are not fully understood. NF-κB is a key transcription factor promoting cancer cell survival, but therapeutically targeting this pathway has proved difficult because NF-κB has pleiotropic functions. Here, we report that MUC13 prevents colorectal cancer cell death by promoting two distinct pathways of NF-kB activation, consequently up-regulating BCL-XL. MUC13 promoted TNF-induced NF-κB activation by interacting with TNFR1 and the E3 ligase, cIAP1, to increase ubiquitination of RIPK1. MUC13 also promoted genotoxin-induced NF-κB activation by increasing phosphorylation of ATM and SUMOylation of NEMO. Moreover, elevated expression of cytoplasmic MUC13 and NF-κB correlated with colorectal cancer progression and metastases. Our demonstration that MUC13 enhances NF-κB signalling in response to both TNF and DNA damaging agents provides a new molecular target for specific inhibition of NF-κB activation. As proof of principle, silencing MUC13 sensitized colorectal cancer cells to death in response to cytotoxic drugs and inflammatory signals and abolished chemotherapy-induced enrichment of CD133+ CD44+ cancer stem cells, slowed xenograft growth in mice, and synergized with 5-fluourouracil to induce tumor regression. Therefore, these data indicate that combining chemotherapy and MUC13 antagonism could improve the treatment of metastatic cancers. Citation Format: Yong H. Sheng, Yaowu He, sumaira Z. hasnain, Ran Wang, Hui Tong, Daniel T. Clarke, Rohan Lourie, Iulia Oancea, kuanyau wong, John W. Lumley, Timothy H. Florin, Philip Sutton, John. D. Hooper, Nigel A. Mcmillan, Michael A. Mcguckin. MUC13 protects colorectal cancer cells from death by activating the NF-κb pathway and is a potential therapeutic target. [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 3564.