Background & Aims: Mesalamine is a mainstay therapeutic agent in chronic ulcerative colitis (CUC) in which condition it reverses crypt architectural changes and reduces colitis-associated cancer (CAC). The present study addressed the possibility that mesalamine reduces β-catenin-associated progenitor cell activation, Akt-phosphorylated β-cateninSer552 (P-β-catenin), and colitis-induced dysplasia (CID). Methods: Effects of mesalamine on P-β-catenin staining and function were assessed by immunohistochemistry and quantitative reverse-transcription polymerase chain reaction (qRT-PCR) in biopsy specimens of CUC in mild or "refractory" severe mucosal inflammation. Effects of mesalamine on epithelial proliferation and activation of Akt and β-catenin were assessed in interleukin (IL)-10-/- colitis and CID by immunohistochemistry 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 that mesalamine reduced Akt activation and P-β-catenin levels in the middle and upper crypt. Reductions in P-β-catenin in CUC biopsy specimens with severe inflammation suggested that mesalamine reduced P-β-catenin levels in tissue refractory to mesalamine's anti-inflammatory effects. In IL-10-/- mice, mesalamine reduced CID concordant with inhibition of crypt Akt and β-catenin signaling. Conclusions: The results are consistent with the model that mesalamine contributes to chemoprevention in CAC by reducing β-catenin signaling within intestinal progenitors.
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