Mesalamine inhibits epithelial beta-catenin activation in chronic ulcerative colitis.
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.
Brown
Jeffrey B
JB
Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Children's Memorial Hospital, Northwestern University, Feinberg School of Medicine, Chicago, Illinois 60611, USA.
Lee
Goo
G
Managlia
Elizabeth
E
Grimm
Gery R
GR
Dirisina
Ramanarao
R
Goretsky
Tatiana
T
Cheresh
Paul
P
Blatner
Nichole R
NR
Khazaie
Khashayarsha
K
Yang
Guang-Yu
GY
Li
Linheng
L
Barrett
Terrence A
TA
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*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D051176:beta Catenin; D016753:Interleukin-10; D019804:Mesalamine