Mesalamine inhibits epithelial beta-catenin activation in chronic ulcerative colitis.

Academic Article

Abstract

  • 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 beta-catenin-associated progenitor cell activation, Akt-phosphorylated beta-catenin(Ser552) (P-beta-catenin), and colitis-induced dysplasia (CID). METHODS: Effects of mesalamine on P-beta-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 beta-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-beta-catenin levels in the middle and upper crypt. Reductions in P-beta-catenin in CUC biopsy specimens with severe inflammation suggested that mesalamine reduced P-beta-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 beta-catenin signaling. CONCLUSIONS: The results are consistent with the model that mesalamine contributes to chemoprevention in CAC by reducing beta-catenin signaling within intestinal progenitors.
  • Authors

    Published In

  • Gastroenterology  Journal
  • Keywords

  • Animals, Anti-Inflammatory Agents, Non-Steroidal, Biopsy, Cell Proliferation, Colitis, Ulcerative, Colon, Disease Models, Animal, Disease Progression, Epithelial Cells, Humans, Interleukin-10, Mesalamine, Mice, Mice, Inbred C57BL, Mice, Knockout, beta Catenin
  • Digital Object Identifier (doi)

    Author List

  • Brown JB; Lee G; Managlia E; Grimm GR; Dirisina R; Goretsky T; Cheresh P; Blatner NR; Khazaie K; Yang G-Y
  • Start Page

  • 595
  • End Page

  • 605.e3
  • Volume

  • 138
  • Issue

  • 2