Title |
MUC13 protects colorectal cancer cells from death by activating the NF-κB pathway and is a potential therapeutic target
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Published in |
Oncogene, July 2016
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DOI | 10.1038/onc.2016.241 |
Pubmed ID | |
Authors |
Y H Sheng, Y He, S Z Hasnain, R Wang, H Tong, D T Clarke, R Lourie, I Oancea, K Y Wong, J W Lumley, T H Florin, P Sutton, J D Hooper, N A McMillan, M A McGuckin |
Abstract |
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.Oncogene advance online publication, 11 July 2016; doi:10.1038/onc.2016.241. |
X Demographics
Geographical breakdown
Country | Count | As % |
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United States | 3 | 60% |
Canada | 1 | 20% |
Australia | 1 | 20% |
Demographic breakdown
Type | Count | As % |
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Members of the public | 5 | 100% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
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Iran, Islamic Republic of | 1 | 2% |
Unknown | 61 | 98% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Researcher | 18 | 29% |
Student > Ph. D. Student | 16 | 26% |
Student > Bachelor | 9 | 15% |
Student > Doctoral Student | 2 | 3% |
Unspecified | 2 | 3% |
Other | 5 | 8% |
Unknown | 10 | 16% |
Readers by discipline | Count | As % |
---|---|---|
Biochemistry, Genetics and Molecular Biology | 21 | 34% |
Medicine and Dentistry | 7 | 11% |
Agricultural and Biological Sciences | 6 | 10% |
Immunology and Microbiology | 4 | 6% |
Pharmacology, Toxicology and Pharmaceutical Science | 3 | 5% |
Other | 8 | 13% |
Unknown | 13 | 21% |