Ligand activation of peroxisome proliferator-activated receptor β inhibits colon carcinogenesis

Holly E. Marin, Marjorie A. Peraza, Andrew N. Billin, Timothy M. Willson, Jerrold M. Ward, Mary J. Kennett, Frank J. Gonzalez, Jeffrey M. Peters

Research output: Contribution to journalArticlepeer-review

107 Scopus citations

Abstract

There is considerable debate whether peroxisome proliferator-activated receptor β/δ (PPARβ/δ) ligands potentiate or suppress colon carcinogenesis. Whereas administration of a PPARβ ligand causes increased small intestinal tumorigenesis in Apcmin/+ mice, PPARβ-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 PPARβ ligand, GW0742. Ligand activation of PPARβ 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 PPARβ-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 PPARβ potentiates intestinal tumorigenesis, here we show that ligand activation of PPARβ attenuates chemically induced colon carcinogenesis and that PPARβ-dependent induction of cathepsin E could explain the reported disparity in the literature about the effect of ligand activation of PPARβ in the intestine.

Original languageEnglish (US)
Pages (from-to)4394-4401
Number of pages8
JournalCancer Research
Volume66
Issue number8
DOIs
StatePublished - Apr 15 2006

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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