The influence of 5-aminosalicylic acid on the progression of colorectal adenomas via the ß-catenin signaling pathway

Munding, Johanna; Ziebarth, Wibke; Pox, Christian P.; Ladigan, Svetlana; Reiser, Markus; Hüppe, Dietrich; Brand, Linda; Schmiegel, Wolff; Tannapfel, Andrea; Reinacher-Schick, Anke C.
March 2012
Carcinogenesis;Mar2012, Vol. 33 Issue 3, p637
Academic Journal
Surveillance colonoscopy is an important strategy for prevention of colorectal cancer. 5-aminosalicylate (ASA) (mesalazine) is discussed as a chemopreventive agent as it reduces the cancer risk in ulcerative colitis patients. The current study analyses the effect of 5-ASA on Wnt/β-catenin signaling in vitro and in vivo in colon epithelial cells. The effect of 5-ASA was determined using a β-catenin/T-cell factor (TCF)-reporter assay and by western blotting in cultured colon cancer cells. Formalin fixed paraffin embedded material from 227 polyps removed from a subgroup of 56 patients, who participated in a randomized placebo-controlled 3-year prevention trial with 5-ASA was evaluated according to histomorphological characteristics and expression of β-catenin and target genes Cox2, cyclin D1 and E-cadherin as well as ornithine decarboxylase (ODC). Patients were grouped into a low-risk and a high-risk group according to the number of adenomas at initial colonoscopy. ß-catenin/TCF signaling activity was significantly reduced by 5-ASA treatment possibly through a reduction in ß-catenin levels. Moreover, 5-ASA significantly reduced ß-catenin levels and nuclear localization in patients’ adenomas. In addition, 5-ASA also significantly changed expression of the downstream targets Cox2, cyclin D1 and E-cadherin, correlating with ß-catenin status. Moreover, 5-ASA significantly reduced levels of ODC in vivo. Expression of p53 was unaltered by the 5-ASA treatment. Our study shows a significant in vitro and long-term in vivo effect of 5-ASA on ß-catenin signaling as a key signaling pathway in the development of colorectal adenoma. Therefore, we suggest the use of 5-ASA as a promising drug for prevention of sporadic colorectal carcinoma.


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