Carcinogenesis Advance Access originally published online on January 16, 2006
Carcinogenesis 2006 27(5):1105-1112; doi:10.1093/carcin/bgi346
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Inhibition of chemically induced skin carcinogenesis by sulindac is independent of peroxisome proliferator-activated receptor-ß/
(PPARß/)
1 Department of Veterinary and Biomedical Sciences and The Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA, 16802, USA, 2 Graduate Program in Molecular Toxicology, The Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, PA, 16802, USA and 3 Laboratory of Metabolism, National Cancer Institute, Bethesda, MD, 20892, USA
* To whom correspondence should be addressed at: 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, USA. Tel: +1 814 863 1387; Fax: +1 814 863 1696; Email: jmp21{at}psu.edu
Inhibition of cyclooxygenase-2 (COX2) by non-steroidal anti-inflammatory drugs (NSAID) is known to suppress skin carcinogenesis. It was further suggested that inhibition of COX2-derived prostaglandins by NSAIDs could reduce levels of putative endogenous ligands of peroxisome proliferator-activated receptor-ß (PPARß), and these ligands could potentiate tumorigenesis. However, it is currently unclear whether ligand activation of PPARß either inhibits or potentiates carcinogenesis. The present studies were designed to examine the mechanism of NSAID-mediated chemoprevention in skin, and, in particular, to determine the role of PPARß in this process. A two-stage skin carcinogenicity bioassay was performed using wild-type and PPARß-null mice that were fed either a control diet or one containing 0.32 g sulindac/kg diet. Significant inhibition of chemically induced skin carcinogenesis was observed in both wild-type and PPARß-null mice, and this was associated with a marked decrease in the concentration of skin prostaglandins including PGE2 and PGI2. Results from these studies demonstrate that inhibition of COX2 by dietary sulindac in mouse skin can effectively inhibit chemically induced skin carcinogenesis, and suggest that the mechanism underlying this chemopreventive effect is independent of PPARß. Additionally, results from these studies do not support the hypothesis that ligand activation of PPARß by COX-derived metabolites potentiates chemically induced skin carcinogenesis.
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