Inhibition of peroxisome proliferator-activated receptor (PPAR)-mediated keratinocyte differentiation by lipoxygenase inhibitors.
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.
Thuillier
Philippe
P
Department of Carcinogenesis, University of Texas M.D. Anderson Cancer Center, Smithville 78957, USA.
Brash
Alan R
AR
Kehrer
James P
JP
Stimmel
Julie B
JB
Leesnitzer
Lisa M
LM
Yang
Peiying
P
Newman
Robert A
RA
Fischer
Susan M
SM
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*
D004791:Enzyme Inhibitors; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D016718:Arachidonic Acid; D007633:Keratins; D019787:Linoleic Acid; D008084:Lipoxygenase