Carcinogenesis Advance Access originally published online on September 1, 2005
Carcinogenesis 2006 27(2):232-239; doi:10.1093/carcin/bgi221
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Carcinogenesis vol.27 no.2 © Oxford University Press 2005; all rights reserved.
NO-donating aspirin isomers downregulate peroxisome proliferator-activated receptor (PPAR)
expression in APCmin/+ mice proportionally to their tumor inhibitory effect: Implications for the role of PPAR in carcinogenesis
Division of Cancer Prevention, Department of Medicine, SUNY at Stony Brook, Stony Brook, NY 11794, USA
* To whom correspondence should be addressed. Division of Cancer Prevention, Life Sciences Building, Room 06, SUNY at Stony Brook, Stony Brook, NY 11794-5200, USA. Tel: +1 631 632 9035; Fax: +1 631 632 1992; Email: basil.rigas{at}stonybrook.edu
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
, 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 expression in Min (multiple intestinal neoplasia) and wild-type mice, and on cell proliferation and apoptosis. PPAR, minimally expressed in wild-type mice, was significantly expressed in Min mice. para NO-ASA inhibited intestinal tumor incidence (59%) and PPAR 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 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, the expression of which may contribute to intestinal carcinogenesis.
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