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
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 o...
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| Language: | English |
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Wiley
2012-01-01
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| Series: | PPAR Research |
| Online Access: | http://dx.doi.org/10.1155/2012/269751 |
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| author | Angelo Cerbone Cristina Toaldo Stefania Pizzimenti Piergiorgio Pettazzoni Chiara Dianzani Rosalba Minelli Eric Ciamporcero Guglielmo Roma Mario Umberto Dianzani Roberto Canaparo Carlo Ferretti Giuseppina Barrera |
| author_facet | Angelo Cerbone Cristina Toaldo Stefania Pizzimenti Piergiorgio Pettazzoni Chiara Dianzani Rosalba Minelli Eric Ciamporcero Guglielmo Roma Mario Umberto Dianzani Roberto Canaparo Carlo Ferretti Giuseppina Barrera |
| author_sort | Angelo Cerbone |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-e6cc84be3dbc471cbf04ecf000cbe337 |
| institution | OA Journals |
| issn | 1687-4757 1687-4765 |
| language | English |
| publishDate | 2012-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | PPAR Research |
| spelling | doaj-art-e6cc84be3dbc471cbf04ecf000cbe3372025-08-20T02:21:04ZengWileyPPAR Research1687-47571687-47652012-01-01201210.1155/2012/269751269751AS601245, 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 CellsAngelo Cerbone0Cristina Toaldo1Stefania Pizzimenti2Piergiorgio Pettazzoni3Chiara Dianzani4Rosalba Minelli5Eric Ciamporcero6Guglielmo Roma7Mario Umberto Dianzani8Roberto Canaparo9Carlo Ferretti10Giuseppina Barrera11MerckSerono Ivrea, Istituto di Ricerche Biomediche “A. Marxer”, RBM S.p.A., 10010 Colleretto Giacosa, ItalyDepartment of Medicine and Experimental Oncology, Section of General Pathology, University of Turin, 10125 Turin, ItalyDepartment of Medicine and Experimental Oncology, Section of General Pathology, University of Turin, 10125 Turin, ItalyDepartment of Medicine and Experimental Oncology, Section of General Pathology, University of Turin, 10125 Turin, ItalyDepartment of Anatomy, Pharmacology and Forensic Medicine, Section of Pharmacology and Pharmacognosy, University of Turin,10125 Turin, ItalyDepartment of Anatomy, Pharmacology and Forensic Medicine, Section of Pharmacology and Pharmacognosy, University of Turin,10125 Turin, ItalyDepartment of Medicine and Experimental Oncology, Section of General Pathology, University of Turin, 10125 Turin, ItalyMerckSerono Ivrea, Istituto di Ricerche Biomediche “A. Marxer”, RBM S.p.A., 10010 Colleretto Giacosa, ItalyDepartment of Medicine and Experimental Oncology, Section of General Pathology, University of Turin, 10125 Turin, ItalyDepartment of Anatomy, Pharmacology, and Forensic Medicine, Section of Pharmacology and Experimental Therapy, University of Turin, 10125 Turin, ItalyDepartment of Anatomy, Pharmacology, and Forensic Medicine, Section of Pharmacology and Experimental Therapy, University of Turin, 10125 Turin, ItalyDepartment of Medicine and Experimental Oncology, Section of General Pathology, University of Turin, 10125 Turin, ItalyPPARαs 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.http://dx.doi.org/10.1155/2012/269751 |
| spellingShingle | Angelo Cerbone Cristina Toaldo Stefania Pizzimenti Piergiorgio Pettazzoni Chiara Dianzani Rosalba Minelli Eric Ciamporcero Guglielmo Roma Mario Umberto Dianzani Roberto Canaparo Carlo Ferretti Giuseppina Barrera 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 PPAR Research |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| url | http://dx.doi.org/10.1155/2012/269751 |
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