Peroxisome proliferators activate growth regulatory pathways largely via peroxisome proliferator-activated receptor alpha-independent mechanisms.
Peroxisome proliferators (PPs) induce liver tumors in rodents through an unknown mechanism requiring PP-activated receptor (PPAR) alpha. Since PPs possess growth modulatory activities that may be important to their hepatocarcinogenicity, we aimed at dissociating the activation of growth signaling pathways from the PPARalpha-mediated response induced by PPs in cultured rat primary hepatocytes. Pretreatment with the differentiation-promoting agent dimethylsulfoxide (DMSO) increased PPARalpha mRNA/protein and enhanced the expression of PPARalpha-regulated genes [fatty acyl Co-A oxidase (FACO), cytochrome P450 4A1 (CYP4A1)] induced by PPs. In contrast, DMSO reduced the expression of immediate early genes (IEG) expression (c-myc, c-jun, c-fos, junB, egr-1) and inhibited mitogen-activated protein kinase (MEK) kinase/extracellular signal-regulated kinases (ERKs) and p38 phosphorylation. Furthermore, the inhibitors Tyrphostin and PD98059 dowregulated IEG/ERKs induction and slightly enhanced the FACO/CYP4A1 response induced by the PP WY-14,643. The stimulation of signal transduction pathways by PPs can be dissociated from PPARalpha activation, thus suggesting that PPs could activate growth regulatory pathways largely via PPARalpha-independent mechanisms.
Pauley
Cindy J
CJ
Department of Genetic and Cellular Toxicology, Merck Research Laboratories, WP 45-308, West Point, PA 19486, USA.
Ledwith
Brian J
BJ
Kaplanski
Catherine
C
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D017874:Immediate-Early Proteins / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020025:Peroxisome Proliferators / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects
D004791:Enzyme Inhibitors; D017874:Immediate-Early Proteins; D020025:Peroxisome Proliferators; D011743:Pyrimidines; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C006253:pirinixic acid; D020928:Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D004121:Dimethyl Sulfoxide