Ligand activation of peroxisome proliferator-activated receptor-beta/delta (PPAR beta/delta) and inhibition of cyclooxygenase 2 (COX2) attenuate colon carcinogenesis through independent signaling mechanisms

Cyclooxygenase (COX) 2-derived prostaglandin E-2 (PGE(2)) promotes colorectal carcinoma growth and invasion, and inhibition of COX2 by non-steroidal anti-inflammatory drugs is known to inhibit these processes. There is controversy regarding the effect of ligand activation of peroxisome proliferator-activated receptor (PPAR)-beta/delta on colon carcinogenesis, although collective evidence from independent laboratories suggest that ligand activation of PPAR beta/delta leads to the induction of terminal differentiation coupled with inhibition of cell growth in a variety of models. The present study examined the hypothesis that ligand activation of PPAR beta/delta and inhibition of COX2 attenuate colon cancer through independent mechanisms and that combining these two mechanisms will enhance this inhibition. Colon cancer was induced by administering azoxymethane to wild-type and PPAR beta/delta-null mice. Cohorts of mice were treated with GW0742 (a PPAR beta/delta ligand), nimesulide (a COX2 inhibitor) or a combination of GW0742 and nimesulide. Inhibition of COX2 by nimesulide attenuated colon cancer and ligand activation of PPAR beta/delta by GW0742 had inhibitory effects. However, the combined treatment of GW0742 and nimesulide did not cause an enhancement in the attenuation of colon cancer. Mechanistically, the effects of these compounds occurred through independent mechanisms as increased levels of differentiation markers as a result of ligand activation of PPAR beta/delta were not found with COX2 inhibition, and a reduction in PGE(2) levels resulting from COX2 inhibition was not observed in response to ligand activation of PPAR beta/delta. Results from these studies effectively dissociate COX2 inhibition and PPAR beta/delta activity during colon carcinogenesis.