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In vitro and in vivo effects of the PPAR-alpha agonists fenofibrate and retinoic acid in endometrial cancer.

ABSTRACT: Fenofibrate, an agonist of PPAR-alpha, in doses above 25 microM, inhibits proliferation and induces apoptosis in Ishikawa endometrial cancer cells. We show that these effects are potentiated by retinoic acid, an agonist of the retinoid-X-receptor. DNA content analysis shows that G1/S phase progression through the cell cycle is inhibited. Independent Component Analysis of gene microarray experiments demonstrated downregulation of Cyclin D1 (CCND1) and associated changes in cell cycle gene expression. Expression of PPAR-alpha mRNA was reduced by >75% using RNA-interference but this resulted in only minor changes in biological effects. A nude mouse model of endometrial carcinoma was used to investigate the effect of fenofibrate in vivo but failed to show consistent inhibition of tumour growth.The combination of fenofibrate and retinoic acid is a potent inhibitor of Ishikawa endometrial cancer cell growth in vitro.

SUBMITTER: Saidi SA

PROVIDER: S-EPMC1475879 | biostudies-literature | 2006 Mar

REPOSITORIES: biostudies-literature

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In vitro and in vivo effects of the PPAR-alpha agonists fenofibrate and retinoic acid in endometrial cancer.

Saidi Samir A SA Holland Cathrine M CM Charnock-Jones D Stephen DS Smith Stephen K SK

Molecular cancer 20060328

<h4>Unlabelled</h4>Fenofibrate, an agonist of PPAR-alpha, in doses above 25 microM, inhibits proliferation and induces apoptosis in Ishikawa endometrial cancer cells. We show that these effects are potentiated by retinoic acid, an agonist of the retinoid-X-receptor. DNA content analysis shows that G1/S phase progression through the cell cycle is inhibited. Independent Component Analysis of gene microarray experiments demonstrated downregulation of Cyclin D1 (CCND1) and associated changes in cell ...[more]

PMID: 16569247

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Project description:Nicotinic acetylcholine receptors (nAChRs) are involved in seizure mechanisms. Hence, nocturnal frontal lobe epilepsy was the first idiopathic epilepsy linked with specific mutations in ?4 or ?2 nAChR subunit genes. These mutations confer gain of function to nAChRs by increasing sensitivity toward acetylcholine. Consistently, nicotine elicits seizures through nAChRs and mimics the excessive nAChR activation observed in animal models of the disease. Treatments aimed at reducing nicotinic inputs are sought as therapies for epilepsies where these receptors contribute to neuronal excitation and synchronization. Previous studies demonstrated that peroxisome proliferator-activated receptors-? (PPAR?), nuclear receptor transcription factors, suppress nicotine-induced behavioral and electrophysiological effects by modulating nAChRs containing ?2 subunits. On these bases, we tested whether PPAR? agonists were protective against nicotine-induced seizures. To this aim we utilized behavioral and electroencephalographic (EEG) experiments in C57BL/J6 mice and in vitro patch clamp recordings from mice and rats. Convulsive doses of nicotine evoked severe seizures and bursts of spike-waves discharges in ?100% of mice. A single dose of the synthetic PPAR? agonist WY14643 (WY, 80 mg/kg, i.p.) or chronic administration of fenofibrate, clinically available for lipid metabolism disorders, in the diet (0.2%) for 14 days significantly reduced or abolished behavioral and EEG expressions of nicotine-induced seizures. Acute WY effects were reverted by the PPAR? antagonist MK886 (3 mg/kg, i.p.). Since neocortical networks are crucial in the generation of ictal activity and synchrony, we performed patch clamp recordings of spontaneous inhibitory postsynaptic currents (sIPSCs) from frontal cortex layer II/III pyramidal neurons. We found that both acute and chronic treatment with PPAR? agonists abolished nicotine-induced sIPSC increases. PPAR? within the CNS are key regulators of neuronal activity through modulation of nAChRs. These effects might be therapeutically exploited for idiopathic or genetically determined forms of epilepsy where nAChRs play a major role.

Project description:BACKGROUND:The role of PPAR? in gene regulation in mouse liver is well characterized. However, less is known about the role of PPAR? in human liver. The aim of the present study was to better characterize the impact of PPAR? activation on gene regulation in human liver. To that end, chimeric mice containing hepatocyte humanized livers were given an oral dose of 300 mg/kg fenofibrate daily for 4 days. Livers were collected and analyzed by hematoxilin and eosin staining, qPCR, and transcriptomics. Transcriptomics data were compared with existing datasets on PPAR? activation in normal mouse liver, human primary hepatocytes, and human precision cut liver slices. RESULTS:Of the different human liver models, the gene expression profile of hepatocyte humanized livers most closely resembled actual human liver. In the hepatocyte humanized mouse livers, the human hepatocytes exhibited excessive lipid accumulation. Fenofibrate increased the size of the mouse but not human hepatocytes, and tended to reduce steatosis in the human hepatocytes. Quantitative PCR indicated that induction of PPAR? targets by fenofibrate was less pronounced in the human hepatocytes than in the residual mouse hepatocytes. Transcriptomics analysis indicated that, after filtering, a total of 282 genes was significantly different between fenofibrate- and control-treated mice (P?<?0.01). 123 genes were significantly lower and 159 genes significantly higher in the fenofibrate-treated mice, including many established PPAR? targets such as FABP1, HADHB, HADHA, VNN1, PLIN2, ACADVL and HMGCS2. According to gene set enrichment analysis, fenofibrate upregulated interferon/cytokine signaling-related pathways in hepatocyte humanized liver, but downregulated these pathways in normal mouse liver. Also, fenofibrate downregulated pathways related to DNA synthesis in hepatocyte humanized liver but not in normal mouse liver. CONCLUSION:The results support the major role of PPAR? in regulating hepatic lipid metabolism, and underscore the more modest effect of PPAR? activation on gene regulation in human liver compared to mouse liver. The data suggest that PPAR? may have a suppressive effect on DNA synthesis in human liver, and a stimulatory effect on interferon/cytokine signalling.

Dataset Information

In vitro and in vivo effects of the PPAR-alpha agonists fenofibrate and retinoic acid in endometrial cancer.

Publications

In vitro and in vivo effects of the PPAR-alpha agonists fenofibrate and retinoic acid in endometrial cancer.

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