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

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 Apc^min/+ 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.