Tauroursodeoxycholic acid attenuates colitis-associated colon cancer by inhibiting nuclear factor kappaB signaling.
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.
['Kim|Young Hoon|YH|', 'Kim|Jee Hyun|JH|http://orcid.org/0000-0003-1019-6345', 'Kim|Byeong Gwan|BG|', 'Lee|Kook Lae|KL|', 'Kim|Ji Won|JW|', 'Koh|Seong-Joon|SJ|']
D000818:Animals D017209:Apoptosis D003092:Colitis D003106:Colon D015179:Colorectal Neoplasms D053582:Interleukin-1alpha D016209:Interleukin-8 D008297:Male D008810:Mice, Inbred C57BL D016328:NF-kappa B D015398:Signal Transduction D013655:Taurochenodeoxycholic Acid D014407:Tumor Cells, Cultured
tauroursodeoxycholic acid inflammatory bowel disease mice NF-kappaB colonic neoplasms