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Carcinogenesis Advance Access published online on August 11, 2007
Carcinogenesis, doi:10.1093/carcin/bgm183
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Published by Oxford University Press 2007.

Peroxisome proliferator-activated receptor-ß/{delta} (PPARß/{delta}) ligands do not potentiate growth of human cancer cell lines

Holly E. Hollingshead*,{dagger}, Renee L. Killins*, Michael G. Borland*,{dagger}, Elizabeth E. Girroir*, Andrew N. Billin§, Timothy M. Willson§, Arun K. Sharma{infty}, Shantu Amin{infty}, Frank J. Gonzalez# and Jeffrey M. Peters1,*,{dagger}

* Department of Veterinary and Biomedical Sciences and The Center of Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, Pennsylvania 16802 USA
{dagger} Graduate Program in Biochemistry, Microbiology, and Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania 16802 USA
§ Nuclear Receptor Discovery Research, GlaxoSmithKline, Research Triangle Park, NC, 27709 USA
{infty} Department of Pharmacology, Penn State Cancer Institute, The Pennsylvania State University, Milton S. Hershey Medical Center, Hershey, Pennsylvania 17033 USA
# Laboratory of Metabolism, National Cancer Institute, Bethesda, Maryland 20892 USA

1 Corresponding author: Jeffrey M. Peters, Ph.D., Department of Veterinary and Biomedical Sciences and Center for Molecular Toxicology and Carcinogenesis, 312 Life Sciences Building, The Pennsylvania State University, University Park, PA 16802, (814) 863-1387, (814) 863-1696 FAX, jmp21{at}psu.edu

Ligands for peroxisome proliferator-activated receptor-ß/{delta} (PPARß/{delta}) increase skeletal muscle fatty acid catabolism, improve insulin sensitivity, increase serum HDL cholesterol, elicit anti-inflammatory activity and induce terminal differentiation. Contradictory findings are also reported suggesting that PPARß/{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 v(with and without serum) or differences in ligands. The present study examined the effect of two different PPARß/{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 PPARß/{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 PPARß/{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 to normal cells, and provide further evidence that PPARß/{delta} ligands do not potentiate tumorigenesis.

Key Words: peroxisome proliferator-activated receptor-ß/{delta} • colon cancer • differentiation • VEGF

Received May 3, 2007; revised July 5, 2007; accepted August 3, 2007.


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