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Experimental Therapeutics, Molecular Targets, and Chemical Biology |
1 Department of Veterinary and Biomedical Sciences and The Center of Molecular Toxicology and Carcinogenesis, and 2 Graduate Program in Biochemistry, Microbiology, and Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania; 3 Nuclear Receptor Discovery Research, GlaxoSmithKline, Research Triangle Park, North Carolina; 4 Infectious Disease Pathogenesis Section, Comparative Medicine Branch and SoBran, Inc., National Institute of Allergy and Infectious Diseases; and 5 Laboratory of Metabolism, National Cancer Institute, Bethesda, Maryland
Requests for reprints: Jeffrey M. Peters, Department of Veterinary and Biomedical Sciences and Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, 312 Life Sciences Building, University Park, PA 16802. Phone: 814-863-1387; Fax: 814-863-1696; E-mail: jmp21{at}psu.edu.
There is considerable debate whether peroxisome proliferator–activated receptor ß/
(PPARß/) ligands potentiate or suppress colon carcinogenesis. Whereas administration of a PPARß ligand causes increased small intestinal tumorigenesis in Apcmin/+ mice, PPARß-null (Pparb–/–) mice exhibit increased colon polyp multiplicity in colon cancer bioassays, suggesting that ligand activation of this receptor will inhibit colon carcinogenesis. This hypothesis was examined by treating wild-type (Pparb+/+) and Pparb–/– with azoxymethane, coupled with a highly specific PPARß ligand, GW0742. Ligand activation of PPARß in Pparb+/+ mice caused an increase in the expression of mRNA encoding adipocyte differentiation–related protein, fatty acid–binding protein, and cathepsin E. These findings are indicative of colonocyte differentiation, which was confirmed by immunohistochemical analysis. No PPARß-dependent differences in replicative DNA synthesis or expression of phosphatase and tensin homologue, phosphoinositide-dependent kinase, integrin-linked kinase, or phospho-Akt were detected in ligand-treated mouse colonic epithelial cells although increased apoptosis was found in GW0742-treated Pparb+/+ mice. Consistent with increased colonocyte differentiation and apoptosis, inhibition of colon polyp multiplicity was also found in ligand-treated Pparb+/+ mice, and all of these effects were not found in Pparb–/– mice. In contrast to previous reports suggesting that activation of PPARß potentiates intestinal tumorigenesis, here we show that ligand activation of PPARß attenuates chemically induced colon carcinogenesis and that PPARß-dependent induction of cathepsin E could explain the reported disparity in the literature about the effect of ligand activation of PPARß in the intestine. (Cancer Res 2006; 66(8): 4394-401)
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