MUC1-C activates the TAK1 inflammatory pathway in colon cancer

Abstract

The mucin 1 (MUC1) oncoprotein has been linked to the inflammatory response by promoting cytokine-mediated activation of the NF-κB pathway. The TGF-β-activated kinase 1 (TAK1) is an essential effector of proinflammatory NF-κB signaling that also regulates cancer cell survival. The present studies demonstrate that the MUC1-C transmembrane subunit induces TAK1 expression in colon cancer cells. MUC1 also induces TAK1 in a MUC1+/−/IL-10−/− mouse model of colitis and colon tumorigenesis. We show that MUC1-C promotes NF-κB-mediated activation of TAK1 transcription and, in a positive regulatory loop, MUC1-C contributes to TAK1-induced NF-κB signaling. In this way, MUC1-C binds directly to TAK1 and confers the association of TAK1 with TRAF6, which is necessary for TAK1-mediated activation of NF-κB. Targeting MUC1-C thus suppresses the TAK1→NF-κB pathway, downregulates BCL-XL, and in turn sensitizes colon cancer cells to MEK inhibition. Analysis of colon cancer databases further indicates that MUC1, TAK1 and TRAF6 are upregulated in tumors associated with decreased survival and that MUC1-C-induced gene expression patterns predict poor outcomes in patients. These results support a model in which MUC1-C-induced TAK1→NF-κB signaling contributes to intestinal inflammation and colon cancer progression.

Raf kinase inhibitor protein mediates intestinal epithelial cell apoptosis and promotes IBDs in humans and mice

“…TAK1-KO in IECs results in intestinal inflammation,40 indicating that TAK1 protects the mice against colitis. Recently, Takahashi reported that the mucin 1 oncoprotein promotes the intestinal inflammation via activating TAK1 signalling,41 indicating that TAK1 signalling promotes colitis. In our study, we have demonstrated that the P-TAK1 level in IECs was robustly enhanced in human IBD and experimental colitis.…”

The Keap1–Nrf2 pathway: promising therapeutic target to counteract ROS-mediated damage in cancers and neurodegenerative diseases

“…Several studies have shown that Nrf2 protects against oxidative stress, chemotherapeutic agents and radiotherapy (Lau et al 2008;Kensler and Wakabayashi 2010;Takahashi et al 2015). However, Nrf2 disruption has enabled the cells towards carcinogens, which lead to the progression of inflammation and, finally, cancer formation (Slocum and Kensler 2011;Takahashi et al 2015).…”

MUC1-C drives MYC in multiple myeloma

“…22 Stabilization of b-catenin by MUC1-C has been confirmed in other studies. 34,[40][41][42][43] In this context, downregulation of MUC1-C in RPMI8226/CRISPR cells was associated with decreased b-catenin levels, but had little effect on the expression of GSK3b (Figure 2A). We also found that b-catenin expression is decreased in U266/CRISPR cells ( Figure 2B).…”

“…34 Briefly, total messenger RNA (mRNA) was extracted using the RNAeasy mini kit (Invitrogen) and complementary DNA (cDNA) was synthesized using the High-Capacity cDNA Reverse Transcription kit (Invitrogen). The cDNA samples were amplified using the SYBR Green qRT-PCR assay kit and the ABI Prism 7000 sequence detector (Applied Biosystems).…”