Carcinogenesis Advance Access published online on January 16, 2006
Carcinogenesis, doi:10.1093/carcin/bgi346
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1 Department of Veterinary and Biomedical Sciences and The Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA, 16802; Graduate Program in Molecular Toxicology, The Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, PA, 16802
* To whom correspondence should be addressed. 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-
Received October 17, 2005
Revised November 23, 2005
Accepted January 13, 2006
CARCINOGENESIS
Inhibition of chemically-induced skin carcinogenesis by sulindac is independent of peroxisome proliferator-activated receptor-
Dae J. Kim 1,
K. Sandeep Prabhu 2,
Frank J. Gonzalez 3,
and
Jeffrey M. Peters 1 *
/
(PPAR/)
2 Department of Veterinary and Biomedical Sciences and The Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA, 16802
3 Laboratory of Metabolism, National Cancer Institute, Bethesda, MD, 20892
Jeffrey M. Peters, E-mail: jmp21{at}psu.edu
Abstract 
(PPAR), and these ligands could potentiate tumorigenesis. However, it is currently unclear whether ligand activation of PPAR 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 PPAR in this process. A two-stage skin carcinogenicity bioassay was performed using wild-type and PPAR-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 PPAR-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 PPAR. Additionally, results from these studies do not support the hypothesis that ligand activation of PPAR by COX-derived metabolites potentiates chemically-induced skin carcinogenesis.
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