title: The PPARβ agonist L-165041 promotes VEGF mRNA stabilization in HPV18-harboring HeLa cells through a receptor-independent mechanism.
abstract: 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 VEGF(121), VEGF(165) and VEGF(189) 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.
authors.affiliation: University of Franche - Comte, F-25000 Besançon, France; EA 3181 - SFR FED 4234, F-25000 Besançon, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Roche
authors.affiliation: University of Franche - Comte, F-25000 Besançon, France; EA 3181 - SFR FED 4234, F-25000 Besançon, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Lascombe
authors.affiliation: University of Franche - Comte, F-25000 Besançon, France; EA 3181 - SFR FED 4234, F-25000 Besançon, France; Department of Urology, CHRU Besançon, F-25000 Besançon, France.
authors.forename: Hugues
authors.initials: H
authors.lastname: Bittard
authors.affiliation: University of Franche - Comte, F-25000 Besançon, France; EA 3181 - SFR FED 4234, F-25000 Besançon, France; Department of Cell and Molecular Biology, CHRU Besançon, F-25000 Besançon, France.
authors.forename: Christiane
authors.initials: C
authors.lastname: Mougin
authors.affiliation: University of Franche - Comte, F-25000 Besançon, France; EA 3181 - SFR FED 4234, F-25000 Besançon, France; Department of Urology, CHRU Besançon, F-25000 Besançon, France. Electronic address: sylvie.fauconnet@univ-fcomte.fr.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Fauconnet
mesh_terms: D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins; D051959:ELAV Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D052161:Human papillomavirus 18 / Q000378:metabolism*; D006801:Humans; D009856:Oncogene Proteins, Viral / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D048068:PPAR-beta / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D010642:Phenoxyacetates / Q000494:pharmacology*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D020871:RNA Stability / Q000187:drug effects*; D012333:RNA, Messenger / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: C520164:4-(3-(2-propyl-3-hydroxy-4-acetyl)phenoxy)propyloxyphenoxy acetic acid; D004268:DNA-Binding Proteins; C052603:E6 protein, Human papillomavirus type 18; D051959:ELAV Proteins; D009856:Oncogene Proteins, Viral; D048068:PPAR-beta; D010642:Phenoxyacetates; D020033:Protein Isoforms; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D042461:Vascular Endothelial Growth Factor A; D048051:p38 Mitogen-Activated Protein Kinases
keywords: ARE; AU-rich element; CHX; Cervical cancer cells; ELAV; ERK(1/2); Embryonic Lethal Abnormal Vision; Extracellular signal Regulated Kinase(1/2); HPV; HuR; Human Papillomavirus; Human antigen R; MAPK; Mitogen-Activated Protein Kinase; PARP; PFT-α; PKC; PMA; PPAR; PPARβ; PPRE; Peroxisome Proliferator Responsive Element; Peroxisome Proliferator-Activated Receptor; Phorbol-12-myristate-13-acetate; Pifithrin-α; PolyADP Ribose Polymerase; Protein Kinase C; RBP; RNA-Binding Protein; RXR; Retinoid X Receptor; TGF-β; TTP; TrisTetraProlin; Tumor Growth Factor–β; VEGF; VEGFR; Vascular Endothelial Growth Factor; Vascular Endothelial Growth Factor Receptor; cycloheximide; mRNA stability; mTOR; mammalian Target Of Rapamycin; p38 MAPK