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Carcinogenesis Advance Access originally published online on September 17, 2008
Carcinogenesis 2008 29(12):2406-2414; doi:10.1093/carcin/bgn219
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Ligand activation of peroxisome proliferator-activated receptor β/{delta} (PPARβ/{delta}) inhibits chemically induced skin tumorigenesis

Moses T. Bility1,2, Meghann K. Devlin-Durante1,2, Nicholas Blazanin1,2, Adam B. Glick1,2, Jerrold M. Ward3, Boo Hyon Kang4, Mary J. Kennett1, Frank J. Gonzalez5 and Jeffrey M. Peters1,2,*

1 Department of Veterinary and Biomedical Sciences and The Center for Molecular Toxicology and Carcinogenesis
2 Integrative Biosciences Graduate Program, Huck Institutes for Life Sciences, The Pennsylvania State University, University Park, PA 16802, USA
3 Infectious Disease Pathogenesis Section, Comparative Medicine Branch and SoBran, Inc., National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA
4 Non-Clinical Pathology Research Center, Medvill, Seoul, Korea 153-801
5 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

Peroxisome proliferator-activated receptor (PPAR)β/{delta}-null mice exhibit enhanced tumorigenesis in a two-stage chemical carcinogenesis model as compared with wild-type mice. Previous work showed that ligand activation of PPARβ/{delta} induces terminal differentiation and inhibits proliferation of primary keratinocytes, and this effect does not occur in the absence of PPARβ/{delta} expression. In the present studies, the effect of ligand activation of PPARβ/{delta} on skin tumorigenesis was examined using both in vivo and ex vivo skin carcinogenesis models. Inhibition of chemically induced skin tumorigenesis was observed in wild-type mice administered GW0742, and this effect was likely the result of ligand-induced terminal differentiation and inhibition of replicative DNA synthesis. These effects were not found in similarly treated PPARβ/{delta}-null mice. Ligand activation of PPARβ/{delta} also inhibited cell proliferation and induced terminal differentiation in initiated/neoplastic keratinocyte cell lines representing different stages of skin carcinogenesis. These studies suggest that topical administration of PPARβ/{delta} ligands may be useful as both a chemopreventive and/or a chemotherapeutic approach to inhibit skin cancer.

Abbreviations: BrdU, bromodeoxyuridine; DMBA, 7,12-dimethylbenz[a]anthracene; mRNA, messenger RNA; PPAR, peroxisome proliferator-activated receptor; qPCR, quantitative real-time PCR; TPA, 12-O-tetradecanoylphorbol-13-acetate; TTA, tetradecylthioacetic acid; UV, ultraviolet

Received June 6, 2008; revised September 8, 2008; accepted September 11, 2008.


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