title: Inhibition of peroxisome proliferator-activated receptor (PPAR)-mediated keratinocyte differentiation by lipoxygenase inhibitors.
abstract: Lipoxygenase (LOX) metabolites from arachidonic acid and linoleic acid have been implicated in atherosclerosis, inflammation, keratinocyte differentiation and tumour progression. We previously showed that peroxisome proliferator-activated receptors (PPARs) play a role in keratinocyte differentiation and that the PPARalpha ligand 8S-hydroxyeicosatetraenoic acid is important in this process. We hypothesized that blocking LOX activity would block PPAR-mediated keratinocyte differentiation. Three LOX inhibitors, nordihydroguaiaretic acid, quercetin and morin, were studied for their effects on primary keratinocyte differentiation and PPAR activity. All three LOX inhibitors blocked calcium-induced expression of the differentiation marker keratin 1. In addition, activity of a PPAR-responsive element was inhibited in the presence of all three inhibitors, and this effect was mediated primarily through PPARalpha and PPARgamma. LOX inhibitors decreased the activity of a chimaeric PPAR-Gal4-ligand-binding domain reporter system and this effect was reversed by addition of PPAR ligands. Ligand-binding studies revealed that the LOX inhibitors bind directly to PPARs and demonstrate a novel mechanism for these inhibitors in altering PPAR-mediated gene expression.
authors.affiliation: Department of Carcinogenesis, University of Texas M.D. Anderson Cancer Center, Smithville 78957, USA.
authors.forename: Philippe
authors.initials: P
authors.lastname: Thuillier
authors.forename: Alan R
authors.initials: AR
authors.lastname: Brash
authors.forename: James P
authors.initials: JP
authors.lastname: Kehrer
authors.forename: Julie B
authors.initials: JB
authors.lastname: Stimmel
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Leesnitzer
authors.forename: Peiying
authors.initials: P
authors.lastname: Yang
authors.forename: Robert A
authors.initials: RA
authors.lastname: Newman
authors.forename: Susan M
authors.initials: SM
authors.lastname: Fischer
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D015152:Blotting, Northern; D015153:Blotting, Western; D002454:Cell Differentiation; D002470:Cell Survival; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017930:Genes, Reporter; D020128:Inhibitory Concentration 50; D015603:Keratinocytes / Q000378:metabolism*; D007633:Keratins / Q000378:metabolism; D008024:Ligands; D019787:Linoleic Acid / Q000378:metabolism; D008084:Lipoxygenase / Q000378:metabolism*; D051379:Mice; D011485:Protein Binding; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D016718:Arachidonic Acid; D007633:Keratins; D019787:Linoleic Acid; D008084:Lipoxygenase