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Carcinogenesis Advance Access published online on September 24, 2007
Carcinogenesis, doi:10.1093/carcin/bgm209
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Published by Oxford University Press 2007.

Ligand activation of peroxisome proliferator-activated receptor-ß/{delta} (PPARß/{delta}) and inhibition of cyclooygenase-2 (COX2) attenuate colon carcinogenesis through independent signaling mechanisms

Holly E. Hollingshead*,{dagger}, Michael G. Borland*,{dagger}, Andrew N. Billin§, Timothy M. Willson§, Frank J. Gonzalez# and Jeffrey M. Peters1,*,{dagger}

* Department of Veterinary and Biomedical Sciences and The Center of Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, Pennsylvania 16802 USA
{dagger} Graduate Program in Biochemistry, Microbiology, and Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania 16802 USA
§ Nuclear Receptor Discovery Research, GlaxoSmithKline, Research Triangle Park, NC, 27709 USA
# Laboratory of Metabolism, National Cancer Institute, Bethesda, Maryland 20892 USA

1 Corresponding author: Jeffrey M. Peters, Ph.D. Department of Veterinary and Biomedical Sciences and Center for Molecular Toxicology and Carcinogenesis, 312 Life Sciences Building, The Pennsylvania State University, University Park, PA 16802, (814) 863-1387, (814) 863-1696 FAX, jmp21{at}psu.edu

Cyclooxygenase 2 (COX2)-derived prostaglandin E2 (PGE2) promotes colorectal carcinoma growth and invasion, and inhibition of COX2 by non-steroidal anti-inflammatory drugs (NSAIDs) is known to inhibit these processes. There is controversy regarding the effect of ligand activation of peroxisome proliferator-activated receptor-ß/{delta} (PPARß/{delta}) on colon carcinogenesis, although collective evidence from independent laboratories suggest that ligand activation of PPARß/{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 PPARß/{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 PPARß/{delta}-null mice. Cohorts of mice were treated with GW0742 (a PPARß/{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 PPARß/{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 PPARß/{delta} were not found with COX2 inhibition, and a reduction in PGE2 levels resulting from COX2 inhibition was not observed in response to ligand activation of PPARß/{delta}. Results from these studies effectively dissociate COX2 inhibition and PPARß/{delta} activity during colon carcinogenesis.

Key Words: peroxisome proliferator-activated receptor-ß/{delta} • colon cancer • cyclooxygenase

Received June 8, 2007; revised August 29, 2007; accepted September 12, 2007.


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