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      Rosiglitazone and AS601245 Decrease Cell Adhesion and Migration through Modulation of Specific Gene Expression in Human Colon Cancer Cells

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          Abstract

          PPARs are nuclear receptors activated by ligands. Activation of PPARγ leads to a reduction of adhesion and motility in some cancer models. PPARγ transcriptional activity can be negatively regulated by JNK-mediated phosphorylation. We postulated that the use of agents able to inhibit JNK activity could increase the effectiveness of PPARγ ligands. We analysed the effects of rosiglitazone (PPARγ ligand) and AS601245 (a selective JNK inhibitor) alone or in association on adhesion and migration of CaCo-2, HT29, and SW480 human colon cancer cells and investigated, through microarray analysis, the genes involved in these processes. Cell adhesion and migration was strongly inhibited by rosiglitazone and AS601245. Combined treatment with the two compounds resulted in a greater reduction of the adhesion and migration capacity. Affymetrix analysis in CaCo-2 cells revealed that some genes which were highly modulated by the combined treatment could be involved in these biological responses. Rosiglitazone, AS601245 and combined treatment down-regulated the expression of fibrinogen chains in all three cell lines. Moreover, rosiglitazone, alone or in association with AS601245, caused a decrease in the fibrinogen release. ARHGEF7/β-PIX gene was highly down-regulated by combined treatment, and western blot analysis revealed that β-PIX protein is down-modulated in CaCo-2, HT29 and SW480 cells, also. Transfection of cells with β-PIX gene completely abrogated the inhibitory effect on cell migration, determined by rosiglitazone, AS601245 and combined treatment. Results demonstrated that β-PIX protein is involved in the inhibition of cell migration and sustaining the positive interaction between PPARγ ligands and anti-inflammatory agents in humans.

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          An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma).

          J Lehmann, L B Moore, T A Smith-Oliver … (1995)
          Thiazolidinedione derivatives are antidiabetic agents that increase the insulin sensitivity of target tissues in animal models of non-insulin-dependent diabetes mellitus. In vitro, thiazolidinediones promote adipocyte differentiation of preadipocyte and mesenchymal stem cell lines; however, the molecular basis for this adipogenic effect has remained unclear. Here, we report that thiazolidinediones are potent and selective activators of peroxisome proliferator-activated receptor gamma (PPAR gamma), a member of the nuclear receptor superfamily recently shown to function in adipogenesis. The most potent of these agents, BRL49653, binds to PPAR gamma with a Kd of approximately 40 nM. Treatment of pluripotent C3H10T1/2 stem cells with BRL49653 results in efficient differentiation to adipocytes. These data are the first demonstration of a high affinity PPAR ligand and provide strong evidence that PPAR gamma is a molecular target for the adipogenic effects of thiazolidinediones. Furthermore, these data raise the intriguing possibility that PPAR gamma is a target for the therapeutic actions of this class of compounds.
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            Anti-inflammatory actions of PPAR ligands: new insights on cellular and molecular mechanisms.

            Daniel S Straus, Hannah Glass (2007)
            The peroxisome proliferator-activated receptors (PPARalpha, -gamma, and -beta/delta) are nuclear receptors with distinct patterns of expression in many cell types both within and outside the immune system. PPAR ligands have anti-inflammatory activity in a variety of mouse models for acute and chronic inflammation. In macrophages, PPARgamma ligands repress expression of a subset of Toll-like receptor (TLR) target genes by a molecular mechanism termed ligand-dependent transrepression. In chronic inflammation, ligand-bound PPARalpha represses production of IFNgamma and IL-17 by CD4(+) T cells, and PPARgamma ligands modulate dendritic cell function to elicit the development of anergic CD4(+) T cells. PPAR ligands also repress expression of cell adhesion molecules on endothelial cells and the secretion of chemokines by epithelial and other cells, decreasing the recruitment of leukocytes to the site of inflammation. The anti-inflammatory activity of PPAR ligands in mouse models suggests their possible use for treating human inflammatory and autoimmune diseases.
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              Peroxisome proliferator-activated receptors alpha and gamma are activated by indomethacin and other non-steroidal anti-inflammatory drugs.

              M Lenhard, Jennifer Oliver, Forrest Ringold … (1997)
              Indomethacin is a non-steroidal anti-inflammatory drug (NSAID) and cyclooxygenase inhibitor that is frequently used as a research tool to study the process of adipocyte differentiation. Treatment of various preadipocyte cell lines with micromolar concentrations of indomethacin in the presence of insulin promotes their terminal differentiation. However, the molecular basis for the adipogenic actions of indomethacin had remained unclear. In this report, we show that indomethacin binds and activates peroxisome proliferator-activated receptor gamma (PPARgamma), a ligand-activated transcription factor known to play a pivotal role in adipogenesis. The concentration of indomethacin required to activate PPARgamma is in good agreement with that required to induce the differentiation of C3H10T1/2 cells to adipocytes. We demonstrate that several other NSAIDs, including fenoprofen, ibuprofen, and flufenamic acid, are also PPARgamma ligands and induce adipocyte differentiation of C3H10T1/2 cells. Finally, we show that the same NSAIDs that activate PPARgamma are also efficacious activators of PPARalpha, a liver-enriched PPAR subtype that plays a key role in peroxisome proliferation. Interestingly, several NSAIDs have been reported to induce peroxisomal activity in hepatocytes both in vitro and in vivo. Our findings define a novel group of PPARgamma ligands and provide a molecular basis for the biological effects of these drugs on adipogenesis and peroxisome activity.
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                Author and article information

                Contributors
                : Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2012
                Publication date (Electronic): 28 June 2012
                Volume: 7
                Issue: 6
                Electronic Location Identifier: e40149
                Affiliations
                [1 ]MerckSerono Ivrea – RBM S.p.A., Istituto di Ricerche Biomediche "A. Marxer", Colleretto Giacosa, Turin, Italy
                [2 ]Section of General Pathology, Department of Medicine and Experimental Oncology, University of Turin, Turin, Italy
                [3 ]Department of Science and Pharmaceutical Technology, University of Turin, Turin, Italy
                Aix-Marseille University, France
                Author notes

                Conceived and designed the experiments: GB CD MUD CT AC. Performed the experiments: AC CT RM EC SP PP CU. Analyzed the data: GR CF. Contributed reagents/materials/analysis tools: CF CD GB AC. Wrote the paper: GB.

                Article
                Publisher ID: PONE-D-12-05192
                DOI: 10.1371/journal.pone.0040149
                PMC ID: 3386191
                PubMed ID: 22761953
                SO-VID: 7922f444-e4ec-4efc-bbb5-b561b7f35ebd
                Copyright © Cerbone et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                Date received : 22 February 2012
                Date accepted : 1 June 2012
                Page count
                Pages: 14
                Categories
                Subject: Research Article
                Subject: Biology
                Subject: Genetics
                Subject: Molecular Genetics
                Subject: Gene Regulation
                Subject: Cancer Genetics
                Subject: Molecular Cell Biology
                Subject: Signal Transduction
                Subject: Signaling in Selected Disciplines
                Subject: Oncogenic Signaling
                Subject: Gene Expression
                Subject: Medicine
                Subject: Drugs and Devices
                Subject: Drug Interactions
                Subject: Gastroenterology and Hepatology
                Subject: Colon
                Subject: Oncology
                Subject: Basic Cancer Research
                Subject: Metastasis
                Subject: Cancer Treatment
                Subject: Chemotherapy and Drug Treatment
                Subject: Cancers and Neoplasms
                Subject: Gastrointestinal Tumors
                Subject: Colon Adenocarcinoma

                ScienceOpen disciplines: Uncategorized
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                ScienceOpen disciplines: Uncategorized

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