Background: Mesalamine, 5-aminosalicylic acid (5-ASA), is a potent antioxidant and is known to enhance peroxisome proliferator–activated receptor γ activity in the intestine. Our previous studies suggested reduced Phosphoinositide 3-Kinase (PI3K)/β-catenin signaling as a mechanism for 5-ASA chemoprevention in chronic ulcerative colitis (CUC). We now hypothesize that 5-ASA mediates changes in intestinal epithelial cell (IEC) reactive oxygen species during colitis to affect phosphatase and tensin homolog (PTEN), PI3K, and β-catenin signaling.
Methods: Here, we examined effects of 5-ASA on oxidant-induced cell signaling pathways in HT-29 cells, IECs from mice, and biopsy tissue from control and CUC patients. Samples were selected to control for inflammation between untreated and 5-ASA–treated CUC patients.
Results: Direct evaluation of IEC in H2O2-stimulated whole colonic crypts indicated that 5-ASA reduces reactive oxygen species levels in lower crypt IECs where long-lived progenitor cells reside. Analysis of biopsies from patient samples revealed that 5-ASA increases expression of the antioxidant catalase in CUC patients. Also, 5-ASA increased nuclear peroxisome proliferator–activated receptor γ protein and target gene expression. Data showed 5-ASA–induced peroxisome proliferator–activated receptor γ DNA binding to the PTEN promoter (chromatin immunoprecipitation) and reduced both phosphorylated and oxidized (inactive) PTEN protein levels. Analysis of patient samples revealed 5-ASA that also reduced levels of active phosphorylated Akt in inflamed colitis tissue. Reduced PI3K/Akt signaling and expression of β-catenin target genes in 5-ASA–treated CUC patients additionally suggests enhanced PTEN activity as well.
Conclusions: Therefore, 5-ASA reduces CUC-induced reactive oxygen species in colonic progenitor cells and enhances PTEN activity, thus attenuating PI3K/Akt signaling. These data suggest that the antioxidant properties of 5-ASA may be the predominant mechanism for 5-ASA chemoprevention.
Article first published online 17 July 2013
Division of Gastroenterology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
Reprints: Terrence A. Barrett, MD, Division of Gastroenterology, Department of Medicine, Northwestern University Feinberg School of Medicine, 676 N. St. Clair, Suite 1400, Chicago, IL 60611 (e-mail: email@example.com).
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The authors have no conflicts of interest to disclose.
Received March 15, 2013
Accepted April 18, 2013