title: Mesalamine inhibits epithelial beta-catenin activation in chronic ulcerative colitis.
abstract: OBJECTIVE
  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.affiliation: Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Children's Memorial Hospital, Northwestern University, Feinberg School of Medicine, Chicago, Illinois 60611, USA.
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Brown
authors.forename: Goo
authors.initials: G
authors.lastname: Lee
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Managlia
authors.forename: Gery R
authors.initials: GR
authors.lastname: Grimm
authors.forename: Ramanarao
authors.initials: R
authors.lastname: Dirisina
authors.forename: Tatiana
authors.initials: T
authors.lastname: Goretsky
authors.forename: Paul
authors.initials: P
authors.lastname: Cheresh
authors.forename: Nichole R
authors.initials: NR
authors.lastname: Blatner
authors.forename: Khashayarsha
authors.initials: K
authors.lastname: Khazaie
authors.forename: Guang-Yu
authors.initials: GY
authors.lastname: Yang
authors.forename: Linheng
authors.initials: L
authors.lastname: Li
authors.forename: Terrence A
authors.initials: TA
authors.lastname: Barrett
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001706:Biopsy; D049109:Cell Proliferation / Q000187:drug effects; D003093:Colitis, Ulcerative / Q000378:metabolism* / Q000473:pathology; D003106:Colon / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D019804:Mesalamine / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D051176:beta Catenin; D016753:Interleukin-10; D019804:Mesalamine