Mesalamine inhibits epithelial beta-catenin activation in chronic ulcerative colitis
Jeffrey B Brown, Goo Lee, Elizabeth Managlia, Gery R Grimm, Ramanarao Dirisina, Tatiana Goretsky, Paul Cheresh, Nichole R Blatner, Khashayarsha Khazaie, Guang-Yu Yang, Linheng Li, Terrence A Barrett, Jeffrey B Brown, Goo Lee, Elizabeth Managlia, Gery R Grimm, Ramanarao Dirisina, Tatiana Goretsky, Paul Cheresh, Nichole R Blatner, Khashayarsha Khazaie, Guang-Yu Yang, Linheng Li, Terrence A Barrett
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.
Conflict of interest statement
Financial Disclosure:
T.A.B. received grant support from Proctor and Gamble for this project. There are no other conflicts of interest to disclose for all authors.
Figures
![Figure 1. 5-ASA treatment reduces P-β-catenin signaling…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2819654/bin/nihms156322f1a.jpg)
![Figure 1. 5-ASA treatment reduces P-β-catenin signaling…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2819654/bin/nihms156322f1b.jpg)
![Figure 2. BrdU incorporation, P-Akt and P-β-catenin…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2819654/bin/nihms156322f2.jpg)
![Figure 3. 5-ASA attenuates epithelial proliferation and…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2819654/bin/nihms156322f3a.jpg)
![Figure 3. 5-ASA attenuates epithelial proliferation and…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2819654/bin/nihms156322f3b.jpg)
![Figure 4. 5-ASA impairs epithelial β-catenin and…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2819654/bin/nihms156322f4.jpg)
![Figure 5. 5-ASA attenuates progression of dysplasia…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2819654/bin/nihms156322f5.jpg)
![Figure 6. 5-ASA reduces epithelial proliferation and…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2819654/bin/nihms156322f6a.jpg)
![Figure 6. 5-ASA reduces epithelial proliferation and…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2819654/bin/nihms156322f6b.jpg)
Source: PubMed