Received for publication July 16, 2008.
Revised August 6, 2008.
Accepted for publication August 6, 2008.

Ligand Activation of Peroxisome Proliferator-Activated Receptor-/ (PPAR/) Inhibits Cell Proliferation in Human HaCaT Keratinocytes

Abstract

While there is strong evidence that ligand activation of PAR/ induces terminal differentiation and attenuates cell growth, some studies suggest that PAR/ actually enhances cell proliferation. For example, it was recently suggested that retinoic acid (RA) is a ligand for PAR/ and potentiates cell proliferation by activating PPAR/. The present study examined the effect of ligand activation of PAR/ on cell proliferation, cell cycle kinetics and target gene expression in human HaCaT keratinocytes using two highly specific PAR/ ligands (GW0742, GW501516) and RA. Both PAR/ ligands and RA inhibited cell proliferation of HaCaT keratinocytes. GW0742 and GW501516 increased expression of known PAR/ target genes while RA did not; RA increased expression of known RAR/RXR target genes while GW0742 did not affect these genes. GW0742, GW501516 and RA did not modulate expression of 3-phosphoinositide-dependent protein kinase (PDPK1) or alter Akt phosphorylation. GW0742 and RA increased annexin V staining as quantitatively determined by flow cytometry. The effects of GW0742 and RA were also examined in wild-type and PAR/-null primary mouse keratinocytes to determine the specific role of PAR/ in modulating cell growth. While inhibition of keratinocyte proliferation by GW0742 was PAR/-dependent, inhibition of cell proliferation by RA occurred in both genotypes. Results from these studies demonstrate that ligand activation of PAR/ inhibits keratinocyte proliferation through PAR/-dependent mechanisms. In contrast, the observed inhibition of cell proliferation in mouse and human keratinocytes by RA is mediated by PAR/-independent mechanisms and is inconsistent with the notion that RA potentiates cell proliferation by activating PAR/.

Key words: PPARs, Apoptosis, Mechanisms of cell killing/apoptosis

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