title: Ligand activation of peroxisome proliferator-activated receptor beta inhibits colon carcinogenesis.
abstract: There is considerable debate whether peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) ligands potentiate or suppress colon carcinogenesis. Whereas administration of a PPARbeta ligand causes increased small intestinal tumorigenesis in Apc(min/+) mice, PPARbeta-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 PPARbeta ligand, GW0742. Ligand activation of PPARbeta 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 PPARbeta-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 PPARbeta potentiates intestinal tumorigenesis, here we show that ligand activation of PPARbeta attenuates chemically induced colon carcinogenesis and that PPARbeta-dependent induction of cathepsin E could explain the reported disparity in the literature about the effect of ligand activation of PPARbeta in the intestine.
authors.affiliation: Department of Veterinary and Biomedical Sciences and The Center of Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, Pennsylvania 16802, USA.
authors.forename: Holly E
authors.initials: HE
authors.lastname: Marin
authors.forename: Marjorie A
authors.initials: MA
authors.lastname: Peraza
authors.forename: Andrew N
authors.initials: AN
authors.lastname: Billin
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Willson
authors.forename: Jerrold M
authors.initials: JM
authors.lastname: Ward
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Kennett
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Peters
mesh_terms: D000818:Animals; D001397:Azoxymethane; D020059:Cathepsin E / Q000096:biosynthesis / Q000235:genetics; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D050556:Fatty Acid-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D008024:Ligands; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D048068:PPAR-beta / Q000819:agonists* / Q000172:deficiency / Q000235:genetics; D000070780:Perilipin-2; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D013844:Thiazoles / Q000378:metabolism / Q000494:pharmacology*; D010636:Phenols; D013438:Sulfhydryl Compounds
chemical_list: D001397:Azoxymethane; D020059:Cathepsin E; D050556:Fatty Acid-Binding Proteins; D008024:Ligands; D008565:Membrane Proteins; D048068:PPAR-beta; D000070780:Perilipin-2; D012333:RNA, Messenger; D013844:Thiazoles; 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