title: Prostaglandin E2 upregulates EGF-stimulated signaling in mitogenic pathways involving Akt and ERK in hepatocytes.
abstract: Prostaglandins (PGs) such as PGE2 enhance proliferation in many cells, apparently through several distinct mechanisms, including transactivation of the epidermal growth factor (EGF) receptor (EGFR) as well as EGFR-independent pathways. In this study we found that in primary cultures of rat hepatocytes PGE2 did not induce phosphorylation of the EGFR, and the EGFR tyrosine kinase blockers gefitinib and AG1478 did not affect PGE2-stimulated phosphorylation of ERK1/2. In contrast, PGE2 elicited EGFR phosphorylation and EGFR tyrosine kinase inhibitor-sensitive ERK phosphorylation in MH1C1 hepatoma cells. These findings suggest that PGE2 elicits EGFR transactivation in MH1C1 cells but not in hepatocytes. Treatment of the hepatocytes with PGE2 at 3 h after plating amplified the stimulatory effect on DNA synthesis of EGF administered at 24 h and advanced and augmented the cyclin D1 expression in response to EGF in hepatocytes. The pretreatment of the hepatocytes with PGE2 resulted in an increase in the magnitude of EGF-stimulated Akt phosphorylation and ERK1/2 phosphorylation and kinase activity, including an extended duration of the responses, particularly of ERK, to EGF in PGE2-treated cells. Pertussis toxin abolished the ability of PGE2 to enhance the Akt and ERK responses to EGF. The results suggest that in hepatocytes, unlike MH1C1 hepatoma cells, PGE2 does not transactivate the EGFR, but instead acts in synergism with EGF by modulating mitogenic mechanisms downstream of the EGFR. These effects seem to be at least in part G(i) protein-mediated and include upregulation of signaling in the PI3K/Akt and the Ras/ERK pathways.
authors.affiliation: Department of Pharmacology, Rikshospitalet, Faculty of Medicine, University of Oslo, Oslo, Norway. olav.dajani@medisin.uio.no
authors.forename: Olav F
authors.initials: OF
authors.lastname: Dajani
authors.forename: Kristin
authors.initials: K
authors.lastname: Meisdalen
authors.forename: Tormod K
authors.initials: TK
authors.lastname: Guren
authors.forename: Monica
authors.initials: M
authors.lastname: Aasrum
authors.forename: Ingun Heiene
authors.initials: IH
authors.lastname: Tveteraas
authors.forename: Peggy
authors.initials: P
authors.lastname: Lilleby
authors.forename: G Hege
authors.initials: GH
authors.lastname: Thoresen
authors.forename: Dagny
authors.initials: D
authors.lastname: Sandnes
authors.forename: Thoralf
authors.initials: T
authors.lastname: Christoffersen
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free; D056741:Cyclin D; D016213:Cyclins / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D066246:ErbB Receptors / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000077156:Gefitinib; D005786:Gene Expression Regulation / Q000187:drug effects*; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology; D008297:Male; D037342:Pertussis Toxin / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects*; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D016895:Culture Media, Serum-Free; D056741:Cyclin D; D016213:Cyclins; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D020032:Tyrphostins; C101044:RTKI cpd; D004815:Epidermal Growth Factor; D004247:DNA; D037342:Pertussis Toxin; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D015232:Dinoprostone; D000077156:Gefitinib