Chemopreventive effect of peroxisome proliferator-activated receptor γ on gastric carcinogenesis in mice

Peroxisome proliferator-activated receptor gamma (PPAR gamma) is known to be expressed in several cancers, and the treatment of these cancer cells with PPAR gamma ligands often induces cell differentiation and apoptosis. Recently, the chemopreventive potential of PPAR gamma ligands on colon carcinogenesis was reported, although the effect of PPAR gamma on colon carcinogenesis and the mechanism of the effect remain controversial. In this study, we attempted to elucidate the role of PPAR gamma in gastric carcinogenesis and explored the possible use of PPAR gamma ligand as a chemopreventive agent for gastric cancer. N-methyl-N-nitrosourea (MNU, 240 ppm) was given in drinking water for 10 weeks to induce gastric cancer in PPAR gamma wild-type (+/+) and heterozygous-deficient (+/-) mice, followed by treatment with PPAR gamma ligand [troglitazone, 0.15% (w/w) in powder food] or the vehicle alone for 42 weeks. At the end of the experiment, PPAR gamma (+/-) mice were more susceptible to MNU-induced gastric cancer than wild-type (+/+) mice (89.5%/55.5%), and troglitazone significantly reduced the incidence of gastric cancer in PPAR gamma (+/+) mice (treatment 55.5%/vehicle 9%) but not in PPAR gamma (+/-) mice. The present study showed that (a) PPAR gamma suppresses gastric carcinogenesis, (b) the PPAR gamma ligand troglitazone is a potential chemopreventive agent for gastric carcinogenesis, and (c) troglitazone's chemopreventative effect is dependent on PPAR gamma.