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.