AS601245, an Anti-Inflammatory JNK Inhibitor, and Clofibrate Have a Synergistic Effect in Inducing Cell Responses and in Affecting the Gene Expression Profile in CaCo-2 Colon Cancer Cells

Angelo Cerbone,Cristina Toaldo,Carlo Ferretti,Chiara Dianzani,Eric Ciamporcero,Stefania Pizzimenti,Guglielmo Roma,Roberto Canaparo,Piergiorgio Pettazzoni,Mario Umberto Dianzani,Giuseppina Barrera,Rosalba Minelli

doi:10.1155/2012/269751

Angelo Cerbone, Cristina Toaldo + Show 10 more

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https://doi.org/10.1155/2012/269751

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Journal: Ppar Research	Publication Date: Jan 1, 2012
Citations: 70	License type: CC BY 3.0

Affiliation: University of Turin

Abstract

PPARαs are nuclear receptors highly expressed in colon cells. They can be activated by the fibrates (clofibrate, ciprofibrate etc.) used to treat hyperlipidemia. Since PPARα transcriptional activity can be negatively regulated by JNK, the inhibition of JNK activity could increase the effectiveness of PPARα ligands. We analysed the effects of AS601245 (a JNK inhibitor) and clofibrate alone or in association, on proliferation, apoptosis, differentiation and the gene expression profile of CaCo-2 human colon cancer cells. Proliferation was inhibited in a dose-dependent way by clofibrate and AS601245. Combined treatment synergistically reduced cell proliferation, cyclin D1 and PCNA expression and induced apoptosis and differentiation. Reduction of cell proliferation, accompanied by the modulation of p21 expression was observed in HepG2 cells, also. Gene expression analysis revealed that some genes were highly modulated by the combined treatment and 28 genes containing PPRE were up-regulated, while clofibrate alone was ineffective. Moreover, STAT3 signalling was strongly reduced by combined treatment. After combined treatment, the binding of PPARα to PPRE increased and paralleled with the expression of the PPAR coactivator MED1. Results demonstrate that combined treatment increases the effectiveness of both compounds and suggest a positive interaction between PPARα ligands and anti-inflammatory agents in humans.

Highlights

PPARs are ligand-activated transcription factors belonging to the nuclear receptor superfamily
We investigated, among the genes activated by clofibrate, by AS601245, and by the combined treatment, the genes having PPRE sequences by using the genomewide library of high-confidence predicted PPAR target genes as published by Lemay and collaborators [21] (Table 2)
Among the top ten genes highly modulated by the combined treatment, the THRA gene, which codifies for the thyroid hormone receptor, has been shown to be related to the apoptosis induction of

Summary

Introduction

PPARs are ligand-activated transcription factors belonging to the nuclear receptor superfamily. Three molecular forms of PPAR have been identified, namely, PPARα, PPARβ/δ, and PPARγ, and all involved in many different biological processes [1]. PPARα is the predominant PPAR subtype highly expressed in liver, heart, proximal tubules of kidney cortex, skeletal muscle, intestinal mucosa, and in brown adipose tissues that are metabolically very active [2]. Endogenous ligands with high specificity for PPARα are long-chain unsaturated fatty acids and fatty acid derivatives [3, 4]. Fibrates, which are hypolipidemic drugs used in the treatment of hyperlipidemia, are among the group of synthetic ligands, which are the most important agonists of PPARα.

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