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

Abstract

Peroxisome proliferator-activated receptor (PPAR)beta/delta-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 PPARbeta/delta induces terminal differentiation and inhibits proliferation of primary keratinocytes, and this effect does not occur in the absence of PPARbeta/delta expression. In the present studies, the effect of ligand activation of PPARbeta/delta 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 PPARbeta/delta-null mice. Ligand activation of PPARbeta/delta 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 PPARbeta/delta ligands may be useful as both a chemopreventive and/or a chemotherapeutic approach to inhibit skin cancer.

Peroxisome Proliferator-Activated Receptor β/δ Cross Talks with E2F and Attenuates Mitosis in HRAS-Expressing Cells

“…Previous work demonstrated that activation of PPAR␤/␦ attenuated skin tumorigenesis in a 2-stage chemical carcinogenesis bioassay and inhibited proliferation of cells with a mutation in the Hras gene (3). This suggests that PPAR␤/␦ could inhibit tumorigenesis through inhibition of oncogenic Hras signaling, which was examined in these studies.…”

“…Consistent with this phenotype, exacerbated skin tumorigenesis was also found in Ppar␤/␦-null mice following a two-stage chemical carcinogenesis bioassay (31). Subsequent studies demonstrated that ligand activation of PPAR␤/␦ inhibits chemically induced tumorigenesis (3,4,68). One mechanism that may underlie these PPAR␤/␦-dependent chemopreventive effects is modulation of epidermal cell proliferation through inhibition of protein kinase C ␣/mitogen-activated protein kinase (PKC␣/MAPK) (31,33).…”

“…Cells were subsequently cultured in control medium or medium containing GW0742 for up to 9 days postinfection. Keratinocytes of the 308 cell line that contain an activated mutation in Hras (56, 65) were cultured as described previously (3,4).…”

“…One mechanism that may underlie these PPAR␤/␦-dependent chemopreventive effects is modulation of epidermal cell proliferation through inhibition of protein kinase C ␣/mitogen-activated protein kinase (PKC␣/MAPK) (31,33). Additionally, ligand activation of PPAR␤/␦ induces terminal differentiation (3,32,61), which influences cell proliferation and skin tumorigenesis.…”

Peroxisome Proliferator-activated Receptor δ Activators Induce IL-8 Expression in Nonstimulated Endothelial Cells in a Transcriptional and Posttranscriptional Manner*

“…It is possible that this dual action also explains the different results concerning the influence of PPAR␦ activators in the treatment and development of various tumor entities. Recently, Bility et al demonstrated that PPAR␦ agonists inhibit chemically induced skin carcinogenesis, whereas Kim et al demonstrated that chemically induced skin carcinogenesis is not influenced by PPAR␦ (29,30). Han et al demonstrated that PPAR␦ agonists induce human lung cancer cell proliferation, whereas He et al found that they do not influence lung cancer cell proliferation (31,32).…”