Tauroursodeoxycholic acid attenuates colitis‐associated colon cancer by inhibiting nuclear factor kappaB signaling

Abstract

Background and Aim Inflammatory bowel diseases is associated with an increased risk for the development of colorectal cancer. However, the mechanism of immune signaling pathways linked to colitis‐associated cancer (CAC) has not been fully elucidated. Tauroursodeoxycholic acid (TUDCA) exhibits anti‐inflammatory and anti‐cancer activities. The aim of this study is to investigate the role of TUDCA in the pathogenesis of CAC. Methods Colitis‐associated cancer was induced in mice using azoxymethane and dextran sodium sulfate administration, and TUDCA's effect on tumor development was evaluated. HCT 116 and COLO 205 were treated with TUDCA or vehicle and then stimulated with tumor necrosis factor‐α (TNF‐α). Expression of interleukin (IL)‐8 was determined by real‐time reverse transcription‐polymerase chain reaction and enzyme‐linked immunosorbent assay, and IκBα phosphorylation and degradation was evaluated by immunoblot assay. The DNA‐binding activity of NF‐κB was assessed by electrophoretic mobility shift assay. Cell viability assay and real‐time reverse transcription‐polymerase chain reaction of bcl‐xL, MCL1, c‐FLIP‐L, and VEGF were performed. Results Tauroursodeoxycholic acid significantly attenuated the development of CAC in mice. Exposure to TUDCA resulted in extensive epithelial apoptosis and reduced levels of phospho‐IκB kinase in the colon. In HCT 116 cells stimulated with TNF‐α, TUDCA significantly inhibited IL‐8 and IL‐1α expression and suppressed TNF‐α‐induced IκBα phosphorylation/degradation and DNA‐binding activity of NF‐κB. Furthermore, in both HCT 116 and COLO 205 cells, TUDCA reduced cell viability and downregulated the expression of bcl‐xL, MCL1, c‐FLIP‐L, and VEGF. Conclusion These results demonstrated that TUDCA suppresses NF‐κB signaling and ameliorates colitis‐associated tumorigenesis, suggesting that TUDCA could be a potential treatment for CAC.

Tauroursodeoxycholate—Bile Acid with Chaperoning Activity: Molecular and Cellular Effects and Therapeutic Perspectives

“…Whereas, in a mice model of CACC, TUDCA-mediated diminution of cancer development was dependent on the reduction of phosphorylated IκB kinase and extensive epithelial apoptosis in the colon of treated animals [181]. Additionally, in TNF-α-stimulated HCT116 cells, TUDCA markedly decreased the expression of IL-8 and IL-1α and inhibited TNF-α-induced phosphorylation/degradation of IκBα together with suppression of NF-κB DNA-binding activity [181]. These studies suggest that TUDCA is able to ameliorate tumorigenesis mostly via alleviation of NF-κB-mediated inflammatory response, thus paving the way for chemopreventive use of this bile acid in oncogenesis of certain carcinomas.…”

“…Thus, it seems counterintuitive to use chemical chaperones such as TUDCA in cancer research, since their cytoprotective potential would rather benefit in maintaining neoplastic cells instead of eliminating them. Paradoxically, several reports from in-vitro and in-vivo studies inform that TUDCA/UDCA might have some favorable effects in therapy of certain types of cancer [175][176][177][178][179][180][181]. Early studies of the influence of TUDCA on growth of human cholangiocarcinoma Mz-ChA-1 cell line demonstrated that TUDCA suppressed the growth of the Mz-ChA-1 cells due to increased calcium signaling and downstream activation of PKC-α-and MAPK p42/44-dependent pathways [175].…”

“…Studies conducted on hepatocellular carcinoma and colitis-associated colon cancer (CACC) have shown that anti-inflammatory activity of TUDCA may underlie its anti-cancer potential [176,181]. In carcinogen-induced liver dysfunction and hepatocellular carcinoma, TUDCA presented chemopreventive properties by preventing ER stress and alleviating hepatic inflammation [176].…”

“…In carcinogen-induced liver dysfunction and hepatocellular carcinoma, TUDCA presented chemopreventive properties by preventing ER stress and alleviating hepatic inflammation [176]. Whereas, in a mice model of CACC, TUDCA-mediated diminution of cancer development was dependent on the reduction of phosphorylated IκB kinase and extensive epithelial apoptosis in the colon of treated animals [181]. Additionally, in TNF-α-stimulated HCT116 cells, TUDCA markedly decreased the expression of IL-8 and IL-1α and inhibited TNF-α-induced phosphorylation/degradation of IκBα together with suppression of NF-κB DNA-binding activity [181].…”

The Role of Interleukins in Colorectal Cancer

“…Therefore, blocking the NF-κB pathway is an idea for the future treatment of CRC. Oroxylin A [19], GEN-27 [20], tauroursodeoxycholic acid (TUDCA) [21] and an ethanol extract obtained from the aerial parts of Artemisia princeps Pampanini cv. Sajabal (EAPP) have been verified as a blocker of the NF-κB pathway, which would inhibit CRC.…”