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

PPARs are nuclear receptors activated by ligands. Activation of PPAR gamma leads to a reduction of adhesion and motility in some cancer models. PPAR gamma 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 PPAR gamma ligands. We analysed the effects of rosiglitazone (PPAR gamma 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/beta-PIX gene was highly down-regulated by combined treatment, and western blot analysis revealed that beta-PIX protein is down-modulated in CaCo-2, HT29 and SW480 cells, also. Transfection of cells with beta-PIX gene completely abrogated the inhibitory effect on cell migration, determined by rosiglitazone, AS601245 and combined treatment. Results demonstrated that beta-PIX protein is involved in the inhibition of cell migration and sustaining the positive interaction between PPAR gamma ligands and anti-inflammatory agents in humans.