5-ASA inhibits epithelial beta-catenin activation in chronic ulcerative colitis.
Gastroenterology
(2009)
In process.
Abstract
BACKGROUND & AIMS:: 5-aminosalicylic acid (5-ASA) is a mainstay therapeutic agent in chronic ulcerative colitis (CUC) where it reverses crypt architectural changes and reduces colitis-associated cancer (CAC). The present study addressed the possibility that 5-ASA reduces beta-catenin-associated progenitor cell activation, Akt-phosphorylated beta-catenin(Ser552) (P-beta-catenin), and colitis-induced dysplasia (CID). METHODS:: Effects of 5-ASA on P-beta-catenin staining and function were assessed by IHC and qRT-PCR in biopsies of CUC in mild or "refractory" severe mucosal inflammation. Effects of 5-ASA on epithelial proliferation, and activation of Akt and beta-catenin were assessed in IL-10(-/-) colitis and CID by IHC and Western blotting. Dysplasia was assessed by counting the number and lengths of lesions per colon. RESULTS:: Data from IL-10(-/-) and human colitis samples show 5-ASA reduced Akt activation and P-beta-catenin levels in the mid and upper crypt. Reductions in P-beta-catenin in CUC biopsies with severe inflammation suggested that 5-ASA reduced P-beta-catenin levels in tissue refractory to 5-ASA's anti-inflammatory effects. In IL-10(-/-) mice, 5-ASA reduced CID concordant with inhibition of crypt Akt and beta-catenin signaling. CONCLUSIONS:: The results are consistent with the model that 5-ASA contributes to chemoprevention in CAC by reducing beta-catenin signaling within intestinal progenitors.
BACKGROUND & AIMS:: 5-aminosalicylic acid (5-ASA) is a mainstay therapeutic agent in chronic ulcerative colitis (CUC) where it reverses crypt architectural changes and reduces colitis-associated cancer (CAC). The present study addressed the possibility that 5-ASA reduces beta-catenin-associated progenitor cell activation, Akt-phosphorylated beta-catenin(Ser552) (P-beta-catenin), and colitis-induced dysplasia (CID). METHODS:: Effects of 5-ASA on P-beta-catenin staining and function were assessed by IHC and qRT-PCR in biopsies of CUC in mild or "refractory" severe mucosal inflammation. Effects of 5-ASA on epithelial proliferation, and activation of Akt and beta-catenin were assessed in IL-10(-/-) colitis and CID by IHC and Western blotting. Dysplasia was assessed by counting the number and lengths of lesions per colon. RESULTS:: Data from IL-10(-/-) and human colitis samples show 5-ASA reduced Akt activation and P-beta-catenin levels in the mid and upper crypt. Reductions in P-beta-catenin in CUC biopsies with severe inflammation suggested that 5-ASA reduced P-beta-catenin levels in tissue refractory to 5-ASA's anti-inflammatory effects. In IL-10(-/-) mice, 5-ASA reduced CID concordant with inhibition of crypt Akt and beta-catenin signaling. CONCLUSIONS:: The results are consistent with the model that 5-ASA contributes to chemoprevention in CAC by reducing beta-catenin signaling within intestinal progenitors.
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Automated medline import. Electronic deposit: 2009-10-28.Electronic publication: 2009-11-03. Publication Date: 2009-10-28. Publication status: aheadofprint. Status: Publisher.
Automated medline import. Electronic deposit: 2009-10-28.Electronic publication: 2009-11-03. Publication Date: 2009-10-28. Publication status: aheadofprint. Status: Publisher.