MUC13 protects colorectal cancer cells from death by activating the NF-kappa B pathway and is a potential therapeutic target

作者：Sheng Y H; He Y; Hasnain S Z; Wang R; Tong H; Clarke D T; Lourie R; Oancea I; Wong K Y; Lumley J W; Florin T H; Sutton P; Hooper J D; McMillan N A; McGuckin M A^*

来源：Oncogene, 2017, 36(5): 700-713.

DOI：10.1038/onc.2016.241

MUC13 is a transmembrane mucin glycoprotein that is over produced by many cancers, although its functions are not fully understood. Nuclear factor-kappa B (NF-kappa B) is a key transcription factor promoting cancer cell survival, but therapeutically targeting this pathway has proved difficult because NF-kappa B has pleiotropic functions. Here, we report that MUC13 prevents colorectal cancer cell death by promoting two distinct pathways of NF-kappa B activation, consequently upregulating BCL-XL. MUC13 promoted tumor necrosis factor (TNF)-induced NF-kappa B activation by interacting with TNFR1 and the E3 ligase, cIAP1, to increase ubiquitination of RIPK1. MUC13 also promoted genotoxin-induced NF-kappa B activation by increasing phosphorylation of ATM and SUMOylation of NF-kappa B essential modulator. Moreover, elevated expression of cytoplasmic MUC13 and NF-kappa B correlated with colorectal cancer progression and metastases. Our demonstration that MUC13 enhances NF-kappa B signaling in response to both TNF and DNA-damaging agents provides a new molecular target for specific inhibition of NFB activation. As proof of principle, silencing MUC13 sensitized colorectal cancer cells to killing by 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.

• 出版日期2017-2-2