The PPARβ agonist L-165041 promotes VEGF mRNA stabilization in HPV18-harboring HeLa cells through a receptor-independent mechanism

Peroxisome Proliferator-Activated Receptor-β (PPARβ) is a ligand-inducible transcription factor activated by both natural (fatty acids and derivatives) and high affinity synthetic agonists. It is thought to play a role in angiogenesis development and Vascular Endothelial Growth Factor (VEGF) regulation but its contribution remains unclear. Until now, the PPARβ agonism effect on VEGF expression in cervical cancer cells was unknown. This led to our interest in assessing the effect of PPARβ activation on the regulation of different VEGF isoforms mRNA expression and the impact of E6 viral oncoprotein and its target p53 on this regulation in cervical cancer cells. Here, we showed that the PPARβ agonist L-165041 induces VEGF121, VEGF165 and VEGF189 expression in HPV (Human Papillomavirus) positive HeLa cells but not in HPV negative cells. The underlying mechanisms did involve neither E6 oncoprotein nor p53. We highlighted a novel mode of PPARβ ligand action including a post-transcriptional regulation of VEGF mRNA expression through the p38 MAPK signaling pathway and the activation of the mRNA-stabilizing factor HuR. But most importantly, we clearly demonstrated that L-165041 acts independently of PPARβ since its effect was not reversed by a chemical inhibition with a specific antagonist and the siRNA-mediated knockdown of the nuclear receptor. As VEGF is crucial for cancer development, the impact of PPARβ ligands on VEGF production is of high importance. Thus, the molecular mechanism of their action has to be elucidated and as a result, PPARβ agonists currently in clinical trials should be carefully monitored.