Ligand activation of peroxisome proliferator-activated receptor β/δ (PPARβ/δ) inhibits chemically induced skin tumorigenesis

Peroxisome proliferator-activated receptor (PPAR)β/δ-null mice exhibit enhanced tumorigenesis in a two-stage chemical carcinogenesis model as compared with wild-type mice. Previous work showed that ligand activation of PPARβ/δ induces terminal differentiation and inhibits proliferation of primary keratinocytes, and this effect does not occur in the absence of PPARβ/δ expression. In the present studies, the effect of ligand activation of PPARβ/δ on skin tumorigenesis was examined using both in vivo and ex vivo skin carcinogenesis models. Inhibition of chemically induced skin tumorigenesis was observed in wild-type mice administered GW0742, and this effect was likely the result of ligand-induced terminal differentiation and inhibition of replicative DNA synthesis. These effects were not found in similarly treated PPARβ/δ-null mice. Ligand activation of PPARβ/δ also inhibited cell proliferation and induced terminal differentiation in initiated/ neoplastic keratinocyte cell lines representing different stages of skin carcinogenesis. These studies suggest that topical administration of PPARβ/δ ligands may be useful as both a chemopreventive and/ or a chemotherapeutic approach to inhibit skin cancer.