Growth regulation of primary human keratinocytes by prostaglandin E receptor EP2 and EP3 subtypes.
We examined the contribution of specific EP receptors in regulating cell growth. By RT-PCR and northern hybridization, adult human keratinocytes express mRNA for three PGE2 receptor subtypes associated with cAMP signaling (EP2, EP3, and small amounts of EP4). In actively growing, non-confluent primary keratinocyte cultures, the EP2 and EP4 selective agonists, 11-deoxy PGE1 and 1-OH PGE1, caused complete reversal of indomethacin-induced growth inhibition. The EP3/EP2 agonist (misoprostol), and the EP1/EP2 agonist (17-phenyl trinor PGE2), showed less activity. Similar results were obtained with agonist-induced cAMP formation. The ability of exogenous dibutyryl cAMP to completely reverse indomethacin-induced growth inhibition support the conclusion that growth stimulation occurs via an EP2 and/or EP4 receptor-adenylyl cyclase coupled response. In contrast, activation of EP3 receptors by sulprostone, which is virtually devoid of agonist activity at EP2 or EP4 receptors, inhibited bromodeoxyuridine uptake in indomethacin-treated cells up to 30%. Although human EP3 receptor variants have been shown in other cell types to markedly inhibit cAMP formation via a pertussis toxin sensitive mechanisms, EP3 receptor activation and presumably growth inhibition was independent of adenylyl cyclase, suggesting activation of other signaling pathways.
Konger
R L
RL
Department of Pathology, Barnes-Jewish Hospital, Washington University School of Medicine, St. Louis, MO 63110, USA.
Malaviya
R
R
Pentland
A P
AP
D000020:Abortifacient Agents, Nonsteroidal / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000187:drug effects; D001973:Bromodeoxyuridine / Q000493:pharmacokinetics; D003994:Bucladesine / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D015870:Gene Expression / Q000235:genetics / Q000502:physiology; D006801:Humans; D007213:Indomethacin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D015603:Keratinocytes / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D016595:Misoprostol / Q000008:administration & dosage / Q000494:pharmacology; D010120:Oxytocics / Q000008:administration & dosage / Q000494:pharmacology; D012313:RNA / Q000032:analysis / Q000235:genetics; D018078:Receptors, Prostaglandin E / Q000235:genetics / Q000502:physiology*; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058308:Receptors, Prostaglandin E, EP3 Subtype; D014158:Transcription, Genetic / Q000235:genetics / Q000502:physiology
D000020:Abortifacient Agents, Nonsteroidal; D016861:Cyclooxygenase Inhibitors; D010120:Oxytocics; C545644:PTGER2 protein, human; C545647:PTGER3 protein, human; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058308:Receptors, Prostaglandin E, EP3 Subtype; D016595:Misoprostol; C016767:sulprostone; D012313:RNA; D003994:Bucladesine; D000262:Adenylyl Cyclases; D001973:Bromodeoxyuridine; D015232:Dinoprostone; D007213:Indomethacin