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Ligand Activation of Peroxisome Proliferator-Activated Receptor-β/ Inhibits Cell Proliferation in Human HaCaT Keratinocytes

Department of Veterinary and Biomedical Sciences and the Center of Molecular Toxicology and Carcinogenesis (M.G.B., E.E.G., J.E.F., J.M.P.), and Graduate Program in Biochemistry, Microbiology, and Molecular Biology (M.G.B., J.M.P.), the Pennsylvania State University, University Park, Pennsylvania; Department of Nutritional Sciences, the Pennsylvania State University, University Park, Pennsylvania (R.Z., A.C.R.); Department of Pharmacology, Penn State Cancer Institute, the Pennsylvania State University, Milton S. Hershey Medical Center, Hershey, Pennsylvania (A.K.S., S.A.); and Laboratory of Metabolism, National Cancer Institute, Bethesda, Maryland (F.J.G.)

Although there is strong evidence that ligand activation of peroxisome proliferator-activated receptor (PPAR)-β/ induces terminal differentiation and attenuates cell growth, some studies suggest that PPARβ/ actually enhances cell proliferation. For example, it was suggested recently that retinoic acid (RA) is a ligand for PPARβ/ and potentiates cell proliferation by activating PPARβ/. The present study examined the effect of ligand activation of PPARβ/ on cell proliferation, cell cycle kinetics, and target gene expression in human HaCaT keratinocytes using two highly specific PPARβ/ ligands [4-[[[2-[3-fluoro-4-(trifluoromethyl)phenyl]-4-methyl-5-thiazolyl]methyl]thio]-2-methylphenoxy acetic acid (GW0742) and 2-methyl-4-((4-methyl-2-(4-trifluoromethylphenyl)-1,3-thiazol-5-yl)-methylsulfanyl)phenoxy-acetic acid (GW501516)] and RA. Both PPARβ/ ligands and RA inhibited cell proliferation of HaCaT keratinocytes. GW0742 and GW501516 increased expression of known PPARβ/ target genes, whereas RA did not; RA increased the expression of known retinoic acid receptor/retinoid X receptor target genes, whereas GW0742 did not affect these genes. GW0742, GW501516, and RA did not modulate the expression of 3-phosphoinositide-dependent protein kinase or alter protein kinase B phosphorylation. GW0742 and RA increased annexin V staining as quantitatively determined by flow cytometry. The effects of GW0742 and RA were also examined in wild-type and PPARβ/-null primary mouse keratinocytes to determine the specific role of PPARβ/ in modulating cell growth. Although inhibition of keratinocyte proliferation by GW0742 was PPARβ/-dependent, inhibition of cell proliferation by RA occurred in both genotypes. Results from these studies demonstrate that ligand activation of PPARβ/ inhibits keratinocyte proliferation through PPARβ/-dependent mechanisms. In contrast, the observed inhibition of cell proliferation in mouse and human keratinocytes by RA is mediated by PPARβ/-independent mechanisms and is inconsistent with the notion that RA potentiates cell proliferation by activating PPARβ/.

Received for publication July 16, 2008.

Accepted for publication August 6, 2008.

Address correspondence to: Dr. Jeffrey M. Peters, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, 312 Life Science Building, University Park, PA 16802. E-mail: jmp21{at}psu.edu

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