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Rosiglitazone and AS601245 decrease cell adhesion and migration through modulation of specific gene expression in
Angelo Cerbone1, Cristina Toaldo, Rosalba Minelli
1MerckSerono Ivrea - RBM SpA, Istituto di Ricerche Biomediche A Marxer, Colleretto Giacosa, Turin, Italy.
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.
Insights
Combining a PPARγ ligand with a JNK inhibitor significantly reduces colon cancer cell adhesion and migration. This synergistic effect involves down-regulation of β-PIX, a key protein in cell migration processes.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors.
- PPARγ activation reduces cancer cell adhesion and motility.
- JNK-mediated phosphorylation negatively regulates PPARγ activity.
Purpose of the Study:
- To investigate if inhibiting JNK activity enhances PPARγ ligand effectiveness.
- To analyze the combined effects of a PPARγ ligand and a JNK inhibitor on colon cancer cell adhesion and migration.
- To identify genes involved in these cellular processes.
Main Methods:
- Utilized rosiglitazone (PPARγ ligand) and AS601245 (JNK inhibitor) on colon cancer cell lines (CaCo-2, HT29, SW480).
- Assessed cell adhesion and migration.
- Performed microarray analysis to identify gene expression changes.
- Conducted Western blot analysis and gene transfection experiments.
Main Results:
- Both rosiglitazone and AS601245 individually inhibited cell adhesion and migration.
- Combined treatment showed a greater reduction in adhesion and migration.
- Down-regulation of fibrinogen chains and release was observed.
- Combined treatment significantly down-regulated ARHGEF7/β-PIX gene and protein.
- β-PIX gene transfection abrogated the inhibitory effects of the treatments on cell migration.
Conclusions:
- Combined PPARγ ligand and JNK inhibitor treatment enhances the inhibition of colon cancer cell migration.
- β-PIX protein plays a crucial role in mediating the anti-migratory effects.
- This highlights a synergistic interaction between PPARγ ligands and anti-inflammatory agents for cancer therapy.
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