title: Peroxisome proliferator-activated receptor-beta/delta (PPARbeta/delta) ligands do not potentiate growth of human cancer cell lines.
abstract: Ligands for peroxisome proliferator-activated receptor-beta/delta (PPARbeta/delta) increase skeletal muscle fatty acid catabolism, improve insulin sensitivity, increase serum high-density lipoprotein cholesterol, elicit anti-inflammatory activity and induce terminal differentiation. Contradictory findings are also reported suggesting that PPARbeta/delta ligands potentiate tumorigenesis by increasing cell proliferation, by inhibiting apoptosis through phosphorylation of Akt and by increasing cyclooxygenase-2 (COX2) and vascular endothelial growth factor (VEGF) expression. The contradictory findings could be due to differences in the model system (cancer cell line versus in vivo), differences in cell culture conditions (with and without serum) or differences in ligands. The present study examined the effect of two different PPARbeta/delta ligands (GW0742 and GW501516) in human cancer cell lines (HT29, HCT116, LS-174T, HepG2 and HuH7) cultured in the presence or absence of serum and compared in vitro analysis with in vivo analysis. Neither PPARbeta/delta ligand increased cell growth or phosphorylation of Akt and no increase in the expression of VEGF or COX2 were detected in any cancer cell line in the presence or absence of serum. Similarly, liver, colon and colon polyps from mice administered these PPARbeta/delta ligands in vivo did not exhibit changes in these markers. Results from these studies demonstrate that serum withdrawal and/or differences in ligands do not underlie the disparity in responses reported in the literature. The quantitative nature of the present findings are inconsistent with the hypothesis that cancer cell lines respond differentially as compared with normal cells, and provide further evidence that PPARbeta/delta ligands do not potentiate tumorigenesis.
authors: Department of Veterinary and Biomedical Sciences and the Center of Molecular Toxicology and Carcinogenesis, Pennsylvania State University, University Park, PA 16802, USA.
authors: Holly E
authors: HE
authors: Hollingshead
authors: Renee L
authors: RL
authors: Killins
authors: Michael G
authors: MG
authors: Borland
authors: Elizabeth E
authors: EE
authors: Girroir
authors: Andrew N
authors: AN
authors: Billin
authors: Timothy M
authors: TM
authors: Willson
authors: Arun K
authors: AK
authors: Sharma
authors: Shantu
authors: S
authors: Amin
authors: Frank J
authors: FJ
authors: Gonzalez
authors: Jeffrey M
authors: JM
authors: Peters
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002471:Cell Transformation, Neoplastic; D003106:Colon / Q000378:metabolism; D003111:Colonic Polyps / Q000378:metabolism; D016895:Culture Media, Serum-Free; D051546:Cyclooxygenase 2 / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D047494:PPAR delta / Q000819:agonists / Q000378:metabolism*; D048068:PPAR-beta / Q000819:agonists / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D010636:Phenols; D013438:Sulfhydryl Compounds
chemical_list: D016895:Culture Media, Serum-Free; D051546:Cyclooxygenase 2; D008024:Ligands; D047494:PPAR delta; D048068:PPAR-beta; D051057:Proto-Oncogene Proteins c-akt; D013844:Thiazoles; D042461:Vascular Endothelial Growth Factor A; C425931:GW 501516; C479979:(4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid; D010636:Phenols; D013438:Sulfhydryl Compounds; C496540:PTGS2 protein, human