Expression and regulation of nonsteroidal anti-inflammatory drug-activated gene (NAG-1) in human and mouse tissue

Background & Aims: Nonsteroidal anti-inflammatory drugs (NSAIDs) induce NSAID-activated gene I (NAG-1), which has proapoptotic and antitumorigenic activities. However, NAG-1 expression and its relationship with apoptosis in human and mouse intestinal tract have not been determined. Methods: NAG-1 expression in human and mouse tissue was determined by immunohistochemistry, and apoptosis was estimated by in situ apoptosis detection. Apoptosis in NAG-1 overexpressing HCT-116 cells was examined with flow cytometry after cell sorting by green fluorescence protein. NAG-1 regulation in mouse cells was examined by Northern blot analysis, comparing sulindac-treated and nontreated mice. Results: Apoptosis was higher in NAG-1 overexpressing cells compared with controls. Human NAG-1 protein was localized to the colonic surface epithelium where cells undergo apoptosis, and higher expression was observed in the normal surface epithelium than in most of the tumors. This localization and lower expression in tumors was similar to that in the Min mouse, in which NSAIDs were also shown to regulate the expression of NAG-1 in mouse cells. Sulindac treatment of mice increased the NAG-1 expression in the colon and liver. Conclusions: Based on these results, we propose that NAG-1 acts as a mediator of apoptosis in intestinal cells and may contribute to cancer chemoprevention by NSAIDs.