Peroxisome-proliferator-activated receptor α agonists inhibit cyclo-oxygenase 2 and vascular endothelial growth factor transcriptional activation in human colorectal carcinoma cells via inhibition of activator protein-1

Abstract

Recent evidence indicates that PPAR (peroxisome-proliferator-activated receptor) alpha ligands possess anti-inflammatory and antitumoural properties owing to their inhibitory effects on the expression of genes that are involved in the inflammatory response. However, the precise molecular mechanisms underlying these effects are poorly understood. In the present study, we show that tumour promoter PMA-mediated induction of genes that are significantly associated with inflammation, tumour growth and metastasis, such as COX-2 (cyclo-oxygenase 2) and VEGF (vascular endothelial growth factor), is inhibited by PPARalpha ligands in the human colorectal carcinoma cell line SW620. PPARalpha activators LY-171883 and WY-14,643 were able to diminish transcriptional induction of COX-2 and VEGF by inhibiting AP-1 (activator protein-1)-mediated transcriptional activation induced by PMA or by c-Jun overexpression. The actions of these ligands on AP-1 activation and COX-2 and VEGF transcriptional induction were found to be dependent on PPARalpha expression. Our studies demonstrate the existence of a negative cross-talk between the PPARalpha- and AP-1-dependent signalling pathways in these cells. PPARalpha interfered with at least two steps within the pathway leading to AP-1 activation. First, PPARalpha activation impaired AP-1 binding to a consensus DNA sequence. Secondly, PPARalpha ligands inhibited c-Jun transactivating activity. Taken together, these findings provide new insight into the anti-inflammatory and anti-tumoural properties of PPARalpha activation, through the inhibition of the induction of AP-1-dependent genes that are involved in inflammation and tumour progression.