Dataset Information

Ligand-activated peroxisome proliferator-activated receptor ?/? modulates human endometrial cancer cell survival.

ABSTRACT: Endometrial cancer is the fourth most common malignancy among women and is a major cause of morbidity contributing to approximately 8,200 annual deaths in the USA. Despite advances to the understanding of endometrial cancer, novel interventions for the disease are necessary given that many tumors become refractory to therapy. As a strategy to identify novel therapies for endometrial carcinoma, in this study, we examined the contribution of the peroxisome proliferator-activated receptor ?/? (PPAR?/?) to endometrial cancer cell proliferation and apoptosis. We found that when activated with the highly selective PPAR?/? agonists, GW0742 and GW501516, PPAR?/? inhibited the proliferation and markedly induced the apoptosis of three endometrial cancer cell lines. The specificity of the PPAR?/?-induced effects on cell proliferation and apoptosis was demonstrated using PPAR?/?-selective antagonists and PPAR?/? small interfering RNA in combination with PPAR?/?-selective agonists. Furthermore, we showed that PPAR?/? activation increased phosphatase and tensin homolog expression, which led to protein kinase B (AKT) and glycogen synthase kinase-3? (GSK3?) dephosphorylation, and increased ?-catenin phosphorylation associated with its degradation. Overall, our data suggest that the antitumorigenic effect of PPAR?/? activation in endometrial cancer is mediated through the negative regulation of the AKT/GSK3?/?-catenin pathway. These findings warrant further investigation of PPAR?/? as a therapeutic target in endometrial cancer.

SUBMITTER: Ma JJ

PROVIDER: S-EPMC3823646 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Ligand-activated peroxisome proliferator-activated receptor β/δ modulates human endometrial cancer cell survival.

Ma J J JJ Monsivais D D Dyson M T MT Coon J S JS Malpani S S Ono M M Zhao H H Xin H H Pavone M E ME Kim J J JJ Chakravarti D D Bulun S E SE

Hormones & cancer 20130814 6

Endometrial cancer is the fourth most common malignancy among women and is a major cause of morbidity contributing to approximately 8,200 annual deaths in the USA. Despite advances to the understanding of endometrial cancer, novel interventions for the disease are necessary given that many tumors become refractory to therapy. As a strategy to identify novel therapies for endometrial carcinoma, in this study, we examined the contribution of the peroxisome proliferator-activated receptor β/δ (PPAR ...[more]

PMID: 23943160

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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-activated peroxisome proliferator-activated receptor ?/? modulates human endometrial cancer cell survival.

Publications

Ligand-activated peroxisome proliferator-activated receptor β/δ modulates human endometrial cancer cell survival.

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