Ligand activation of peroxisome proliferator-activated receptor beta/delta (PPAR beta/delta) inhibits chemically induced skin tumorigenesis.
Peroxisome proliferator-activated receptor (PPAR)beta/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 PPARbeta/delta induces terminal differentiation and inhibits proliferation of primary keratinocytes, and this effect does not occur in the absence of PPARbeta/delta expression. In the present studies, the effect of ligand activation of PPARbeta/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 PPARbeta/delta-null mice. Ligand activation of PPARbeta/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 PPARbeta/delta ligands may be useful as both a chemopreventive and/or a chemotherapeutic approach to inhibit skin cancer.
Bility
Moses T
MT
Department of Veterinary and Biomedical Sciences and the Center for Molecular Toxicology and Carcinogenesis, Pennsylvania State University, University Park, PA 16802, USA.
Devlin-Durante
Meghann K
MK
Blazanin
Nicholas
N
Glick
Adam B
AB
Ward
Jerrold M
JM
Kang
Boo Hyon
BH
Kennett
Mary J
MJ
Gonzalez
Frank J
FJ
Peters
Jeffrey M
JM
D000096:Acetone / Q000633:toxicity; D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D004789:Enzyme Activation / Q000502:physiology; D005260:Female; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008024:Ligands; D051379:Mice; D008817:Mice, Mutant Strains; D047494:PPAR delta / Q000378:metabolism*; D048068:PPAR-beta / Q000378:metabolism*; D012878:Skin Neoplasms / Q000139:chemically induced / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity; D013844:Thiazoles / Q000633:toxicity; D010636:Phenols; D013438:Sulfhydryl Compounds
D000096:Acetone; D002273:Carcinogens; D008024:Ligands; D047494:PPAR delta; D048068:PPAR-beta; D013755:Tetradecanoylphorbol Acetate; D013844:Thiazoles; C479979:(4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid; D010636:Phenols; D013438:Sulfhydryl Compounds
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