Dataset Information

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

ABSTRACT: MUC13 is a transmembrane mucin glycoprotein that is over produced by many cancers, although its functions are not fully understood. Nuclear factor-?B (NF-?B) is a key transcription factor promoting cancer cell survival, but therapeutically targeting this pathway has proved difficult because NF-?B 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-X_L. MUC13 promoted tumor necrosis factor (TNF)-induced NF-?B activation by interacting with TNFR1 and the E3 ligase, cIAP1, to increase ubiquitination of RIPK1. MUC13 also promoted genotoxin-induced NF-?B activation by increasing phosphorylation of ATM and SUMOylation of NF-?B essential modulator. Moreover, elevated expression of cytoplasmic MUC13 and NF-?B correlated with colorectal cancer progression and metastases. Our demonstration that MUC13 enhances NF-?B signaling in response to both TNF and DNA-damaging agents provides a new molecular target for specific inhibition of NF-?B 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.

SUBMITTER: Sheng YH

PROVIDER: S-EPMC5541270 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Sheng Y H YH He Y Y Hasnain S Z SZ Wang R R Tong H H Clarke D T DT Lourie R R Oancea I I Wong K Y KY Lumley J W JW Florin T H TH Sutton P P Hooper J D JD McMillan N A NA McGuckin M A MA

Oncogene 20160711 5

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-X<sub>L</sub>. MUC13 pro ...[more]

PMID: 27399336

Similar Datasets

Project description:Brain damage following cerebral ischemia-reperfusion (I/R) is a complicated pathophysiological course, in which inflammation and oxidative stress have been suggested to serve an important role. Toll-like receptor 4 (TLR4) has been suggested to be involved in secondary inflammatory process in cerebral ischemia. Nuclear factor erythroid 2-related factor 2 (Nrf2), an important regulator of the antioxidant host defense, maintains the cellular redox homeostasis. Tissue kallikrein (TK) has been proven to elicit a variety of biological effects in ischemic stroke through its anti-inflammatory and anti-oxidant properties. However, the mechanisms underlying its beneficial effects remain poorly defined. The present study examined the hypothesis that TK attenuates ischemic cerebral injury via the TLR4/nuclear factor-κB (NF-κB) and Nrf2 signaling pathways. Using a transient rat middle cerebral artery occlusion (MCAO) model, the effects of immediate and delayed TK treatment subsequent to reperfusion were investigated. The neurological deficits, infarct size, and the expression of TLR4/NF-κB and Nrf2 pathway in ischemic brain tissues were measured at 24 following MCAO. The results indicated that TK immediate treatment significantly improved neurological deficits and reduced the infarct size, accompanied by the inhibition of TLR4 and NF-κB levels, and the activation of Nrf2 pathway. Furthermore, TK delayed treatment also exerted neuroprotection against I/R injury. However, the neuroprotective effect of TK immediate treatment was better compared with that of TK delayed treatment. In conclusion, the results indicated that TK protected the brain against ischemic injury in rats after MCAO through its anti-oxidative and anti-inflammatory effects. Suppression of TLR4/NF-κB and activation of the Nrf2 pathway contributed to the neuroprotective effects induced by TK in cerebral ischemia. Therefore, TK may provide an effective intervention with a wider therapeutic window for ischemic stroke.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets