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

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Sheng, YH; He, Y; Hasnain, SZ; Wang, R; Tong, H; Clarke, DT; Lourie, R; Oancea, I; Wong, KY; Lumley, JW; ...Date
2017-02-02Source Title
OncogenePublisher
NATURE PUBLISHING GROUPAffiliation
Paediatrics (RCH)Microbiology and Immunology
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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. (2017). MUC13 protects colorectal cancer cells from death by activating the NF-kappa B pathway and is a potential therapeutic target. ONCOGENE, 36 (5), pp.700-713. https://doi.org/10.1038/onc.2016.241.Access Status
Open AccessAbstract
MUC13 is a transmembrane mucin glycoprotein that is over produced by many cancers, although its functions are not fully understood. Nuclear factor-κB (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 upregulating BCL-XL. MUC13 promoted tumor necrosis factor (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 NF-κB essential modulator. Moreover, elevated expression of cytoplasmic MUC13 and NF-κB correlated with colorectal cancer progression and metastases. Our demonstration that MUC13 enhances NF-κB signaling 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 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.
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