Ligand activation of peroxisome proliferator-activated receptor-β/δ(PPARβ/δ) inhibits cell growth of human N/TERT-1 keratinocytes

The functional role of peroxisome proliferator-activated receptor-β(PPARβ; also referred to as PPARδ) in epidermal cell growth remains controversial. Recent evidence suggests that ligand activation of PPARβ/δ increases cell growth and inhibits apoptosis in epidermal cells. In contrast, other reports suggest that ligand activation of PPARβ/δ leads to the induction of terminal differentiation and inhibition of cell growth. In the present study, the effect of the highly specific PPARβ/δ ligand GW0742 on cell growth was examined using a human keratinocyte cell line (N/TERT-1) and mouse primary keratinocytes. Ligand activation of PPARβ/δ with GW0742 prevented cell cycle progression from G1 to S phase and attenuated cell proliferation in N/TERT-1 cells. Despite specifically activating PPARβ/δ as revealed by target gene induction, no changes in PTEN, PDK and ILK expression or downstream phosphorylation of Akt were found in either N/TERT-1 cells or primary keratinocytes. Further, altered cell growth resulting from serum withdrawal and the induction of caspase-3 activity by ultraviolet radiation were unchanged in the absence of PPARβ/δ expression and/or the presence of GW0742. While no changes in the expression of mRNAs encoding cell cycle control proteins were found in response to GW0742, a significant decrease in the level of ERK phosphorylation was observed. Results from these studies demonstrate that ligand activation of PPARβ/δ does not lead to an anti-apoptotic effect in either human or mouse keratinocytes, but rather, leads to inhibition of cell growth likely through the induction of terminal differentiation.