Ligand activation of peroxisome proliferator-activated receptor-beta/delta(PPARbeta/delta) inhibits cell growth of human N/TERT-1 keratinocytes.
The functional role of peroxisome proliferator-activated receptor-beta(PPARbeta; also referred to as PPARdelta) in epidermal cell growth remains controversial. Recent evidence suggests that ligand activation of PPARbeta/delta increases cell growth and inhibits apoptosis in epidermal cells. In contrast, other reports suggest that ligand activation of PPARbeta/delta leads to the induction of terminal differentiation and inhibition of cell growth. In the present study, the effect of the highly specific PPARbeta/delta ligand GW0742 on cell growth was examined using a human keratinocyte cell line (N/TERT-1) and mouse primary keratinocytes. Ligand activation of PPARbeta/delta with GW0742 prevented cell cycle progression from G1 to S phase and attenuated cell proliferation in N/TERT-1 cells. Despite specifically activating PPARbeta/delta 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 PPARbeta/delta 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 PPARbeta/delta 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.
Burdick
Andrew D
AD
Department of Veterinary and Biomedical Sciences and The Center for Molecular Toxicology and Carcinogenesis, The Huck Institute of Life Sciences, The Pennsylvania State University, University Park 16802, United States.
Bility
Moses T
MT
Girroir
Elizabeth E
EE
Billin
Andrew N
AN
Willson
Timothy M
TM
Gonzalez
Frank J
FJ
Peters
Jeffrey M
JM
D064413:3-Phosphoinositide-Dependent Protein Kinases; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D015603:Keratinocytes / Q000166:cytology* / Q000187:drug effects* / Q000201:enzymology / Q000528:radiation effects; D008024:Ligands; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D047494:PPAR delta / Q000378:metabolism*; D048068:PPAR-beta / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D019098:Telomerase / Q000378:metabolism*; D013844:Thiazoles / Q000494:pharmacology*; D015533:Transcriptional Activation; D014466:Ultraviolet Rays; D010636:Phenols; D013438:Sulfhydryl Compounds
D064413:3-Phosphoinositide-Dependent Protein Kinases; D018797:Cell Cycle Proteins; D008024:Ligands; D047494:PPAR delta; D048068:PPAR-beta; D051059:PTEN Phosphohydrolase; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D019098:Telomerase; D013844:Thiazoles; C479979:(4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid; D010636:Phenols; D013438:Sulfhydryl Compounds; C509186:TERT protein, human