Carcinogenesis Advance Access originally published online on September 24, 2007
Carcinogenesis 2008 29(1):169-176; doi:10.1093/carcin/bgm209
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Ligand activation of peroxisome proliferator-activated receptor-β/
(PPARβ/) and inhibition of cyclooxygenase 2 (COX2) attenuate colon carcinogenesis through independent signaling mechanisms
1 Department of Veterinary and Biomedical Sciences and The Center of Molecular Toxicology and Carcinogenesis
2 Graduate Program in Biochemistry, Microbiology, and Molecular Biology, The Pennsylvania State University, University Park, PA 16802, USA
3 Nuclear Receptor Discovery Research, GlaxoSmithKline, Research Triangle Park, NC 27709, USA
4 Laboratory of Metabolism, National Cancer Institute, Bethesda, MD 20892, USA
* To whom correspondence should be addressed. Tel: +1 814 863 1387; Fax: +1 814 863 1696; Email: jmp21{at}psu.edu
Cyclooxygenase (COX) 2-derived prostaglandin E2 (PGE2) 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)-β/
on colon carcinogenesis, although collective evidence from independent laboratories suggest that ligand activation of PPARβ/ 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 PPARβ/ 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 PPARβ/-null mice. Cohorts of mice were treated with GW0742 (a PPARβ/ ligand), nimesulide (a COX2 inhibitor) or a combination of GW0742 and nimesulide. Inhibition of COX2 by nimesulide attenuated colon cancer and ligand activation of PPARβ/ 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 PPARβ/ 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 PPARβ/. Results from these studies effectively dissociate COX2 inhibition and PPARβ/ activity during colon carcinogenesis.
Abbreviations: APC, adenomatous polyposis coli; ADRP, adipocyte differentiation-related protein; ANGPTL4, angiogenin-related protein-like 4; AOM, azoxymethane; BrdU, bromodeoxyuridine; COX, cyclooxygenase; CRC, colorectal cancer; mRNA, messenger RNA; NSAID, non-steroidal anti-inflammatory drugs; PCR, polymerase chain reaction; PGE2, prostaglandin E2; PPAR, peroxisome proliferator-activated receptor
Received June 8, 2007; revised August 29, 2007; accepted September 12, 2007.
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