Journal
CANCER RESEARCH
Volume 66, Issue 8, Pages 4394-4401Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-05-4277
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- NCI NIH HHS [CA97999, CA89607] Funding Source: Medline
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There is considerable debate whether peroxisome proliferator-activated receptor beta/delta (PPAR beta/delta) ligands potentiate or suppress colon carcinogenesis. Whereas administration of a PPAR beta ligand causes increased small intestinal tumorigenesis in Apc(min/+) mice, PPAR beta-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 PPAR beta ligand, GW0742. Ligand activation of PPAR beta 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 PPAR beta-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 PPAR beta potentiates intestinal tumorigenesis, here we show that ligand activation of PPAR beta attenuates chemically induced colon carcinogenesis and that PPAR beta-dependent induction of cathepsin E could explain the reported disparity in the literature about the effect of ligand activation of PPAR beta in the intestine.
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