Biochem. J. (2006) 395
(81–88) (Printed in Great Britain)
Peroxisome-proliferator-activated receptor a agonists inhibit cyclo-oxygenase 2 and vascular endothelial growth factor transcriptional activation in human colorectal carcinoma cells via inhibition of activator protein-1
Raquel GRAU, Carmen PUNZÓN, Manuel FRESNO and Miguel A. IÑIGUEZ1
Centro de Biología Molecular “Severo Ochoa”, Departamento de Biología Molecular. Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain
Recent evidence indicates that PPAR (peroxisome-proliferator-activated receptor) a 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 PPARa ligands in the human colorectal carcinoma cell line SW620. PPARa 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 PPARa expression. Our studies demonstrate the existence of a negative cross-talk between the PPARa- and AP-1-dependent signalling pathways in these cells. PPARa interfered with at least two steps within the pathway leading to AP-1 activation. First, PPARa activation impaired AP-1 binding to a consensus DNA sequence. Secondly, PPARa ligands inhibited c-Jun transactivating activity. Taken together, these findings provide new insight into the anti-inflammatory and anti-tumoural properties of PPARa activation, through the inhibition of the induction of AP-1-dependent genes that are involved in inflammation and tumour progression.
Key words: cyclo-oxygenase 2 (COX-2), LY-171883, peroxisome-proliferator-activated receptor a (PPARa), SW620 cell, vascular endothelial growth factor (VEGF), WY-14,643.
Abbreviations used: AP-1, activator protein-1; Apc, adenomatous polyposis coli; COX, cyclo-oxygenase; DBD, DNA-binding domain; EMSA, electrophoretic mobility-shift assay; FBS, foetal bovine serum; Ion, A23187 calcium ionophore; JNK, c-Jun N-terminal kinase; MEM, minimal essential medium; NF-kB, nuclear factor kB; NSAID, non-steroidal anti-inflammatory drug; 15d-PGJ2, 15-deoxy-D12,14-prostaglandin J2; PPAR, peroxisome-proliferator-activated receptor; PPRE, peroxisome-proliferator-response element; RLU, relative luciferase units; RT, reverse transcription; VEGF, vascular endothelial growth factor.
1To whom correspondence should be addressed (email Mainiguez@cbm.uam.es).
Received 17 June 2005/25 November 2005; accepted 13 December 2005
Published as BJ Immediate Publication 13 December 2005, doi:10.1042/BJ20050964
The Biochemical Society, London ©2006
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