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Ligand activation of peroxisome proliferator-activated receptor beta/delta (PPAR beta/delta) inhibits chemically induced skin tumorigenesis.

ABSTRACT: 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.

SUBMITTER: Bility MT

PROVIDER: S-EPMC2722866 | biostudies-other | 2008 Dec

REPOSITORIES: biostudies-other

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Ligand activation of peroxisome proliferator-activated receptor beta/delta (PPAR beta/delta) inhibits chemically induced skin tumorigenesis.

Bility Moses T MT 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

Carcinogenesis 20080917 12

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 w ...[more]

PMID: 18799709

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Project description:Although there is strong evidence that ligand activation of peroxisome proliferator-activated receptor (PPAR)-beta/delta induces terminal differentiation and attenuates cell growth, some studies suggest that PPARbeta/delta actually enhances cell proliferation. For example, it was suggested recently that retinoic acid (RA) is a ligand for PPARbeta/delta and potentiates cell proliferation by activating PPARbeta/delta. The present study examined the effect of ligand activation of PPARbeta/delta on cell proliferation, cell cycle kinetics, and target gene expression in human HaCaT keratinocytes using two highly specific PPARbeta/delta 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 PPARbeta/delta ligands and RA inhibited cell proliferation of HaCaT keratinocytes. GW0742 and GW501516 increased expression of known PPARbeta/delta 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 PPARbeta/delta-null primary mouse keratinocytes to determine the specific role of PPARbeta/delta in modulating cell growth. Although inhibition of keratinocyte proliferation by GW0742 was PPARbeta/delta-dependent, inhibition of cell proliferation by RA occurred in both genotypes. Results from these studies demonstrate that ligand activation of PPARbeta/delta inhibits keratinocyte proliferation through PPARbeta/delta-dependent mechanisms. In contrast, the observed inhibition of cell proliferation in mouse and human keratinocytes by RA is mediated by PPARbeta/delta-independent mechanisms and is inconsistent with the notion that RA potentiates cell proliferation by activating PPARbeta/delta.

Project description:Peroxisome proliferator-activated receptor (PPAR) beta/delta-null mice exhibit exacerbated hepatotoxicity in response to administration of carbon tetrachloride (CCl(4)). To determine whether ligand activation of the receptor protects against chemical toxicity in the liver, wild-type and PPARbeta/delta-null mice were administered CCl(4) with or without coadministration of the highly specific PPARbeta/delta ligand GW0742. Biomarkers of liver toxicity, including serum alanine aminotransferase (ALT) and hepatic tumor necrosis factor (TNF) alpha mRNA, were significantly higher in CCl(4)-treated PPARbeta/delta-null mice compared to wild-type mice. Hepatic expression of TNF-like weak inducer of apoptosis receptor (TWEAKr) and S100 calcium-binding protein A6 (S100A6/calcyclin), genes involved in nuclear factor kappa B signaling, was higher in the CCl(4)-treated PPARbeta/delta-null mice compared to wild-type mice. GW0742 treatment resulted in reduced serum ALT concentration and lower expression of CCl(4)-induced TNF-alpha, S100A6, monocyte chemoattractant protein-1 (MCP1), and TWEAKr in wild-type mice, and these effects were not observed in PPARbeta/delta-null mice. Expression of TNF-alpha was higher in PPARbeta/delta-null primary hepatocytes in response to interleukin-1beta treatment compared to wild-type hepatocytes, but GW0742 did not significantly modulate TNF-alpha expression in hepatocytes from either genotype. While PPARbeta/delta-null hepatic stellate exhibited higher rates of proliferation compared to wild-type cells, GW0742 did not affect alpha-smooth muscle actin expression in these cells. Combined, these findings demonstrate that ligand activation of PPARbeta/delta protects against chemically induced hepatotoxicity by downregulating expression of proinflammatory genes. Hepatocytes and hepatic stellate cells do not appear to directly mediate the inhibitory effects of ligand activation of PPARbeta/delta in liver, suggesting the involvement of paracrine and autocrine events mediated by hepatic cells.

Dataset Information

Ligand activation of peroxisome proliferator-activated receptor beta/delta (PPAR beta/delta) inhibits chemically induced skin tumorigenesis.

Publications

Ligand activation of peroxisome proliferator-activated receptor beta/delta (PPAR beta/delta) inhibits chemically induced skin tumorigenesis.

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