NO-donating aspirin isomers downregulate peroxisome proliferator-activated receptor (PPAR)δ expression in APCmin/+ mice proportionally to their tumor inhibitory effect:: Implications for the role of PPARδ in carcinogenesis

Nitric oxide donating aspirin (NO-ASA), consisting of a traditional ASA to which a NO-releasing moiety is covalently attached, is a promising chemopreventive agent against colon cancer. Its mechanism of action is not fully delineated. Here we examined its effect on the expression of the nuclear receptor PPAR delta, whose role in colon carcinogenesis remains highly controversial. We studied histochemically the effect of the meta and para positional isomers of NO-ASA on PPAR delta expression in Min (multiple intestinal neoplasia) and wild-type mice, and on cell proliferation and apoptosis. PPAR delta, minimally expressed in wild-type mice, was significantly expressed in Min mice. para NO-ASA inhibited intestinal tumor incidence (59%) and PPAR delta expression (55.3%) more than meta NO-ASA (38 and 41.5%, respectively). Neither isomer affected cell proliferation, but both induced apoptosis in Min mice (para 52.5% for normal mucosa and 70.3% for tumors; meta 31.4 and 21.9%, respectively). The changes in PPAR delta expression correlated significantly with changes in apoptosis. Furthermore, NO-ASA induced areas of necrosis in intestinal tumors are probably resulting from the induction of atypical apoptosis. Our data suggest that NO-ASA suppresses intestinal tumorigenesis possibly in part through its inhibitory effect on PPAR delta, the expression of which may contribute to intestinal carcinogenesis.