title: Antagonism of the prostaglandin E2 EP1 receptor in MDCK cells increases growth through activation of Akt and the epidermal growth factor receptor.
abstract: The actions of prostaglandin E2 (PGE2) in the kidney are mediated by G protein-coupled E-prostanoid (EP) receptors, which affect renal growth and function. This report examines the role of EP receptors in mediating the effects of PGE2 on Madin-Darby canine kidney (MDCK) cell growth. The results indicate that activation of Gs-coupled EP2 and EP4 by PGE2 results in increased growth, while EP1 activation is growth inhibitory. Indeed, two EP1 antagonists (ONO-8711 and SC51089) stimulate, rather than inhibit, MDCK cell growth, an effect that is lost following an EP1 knockdown. Similar observations were made with M1 collecting duct and rabbit kidney proximal tubule cells. ONO-8711 even stimulates growth in the absence of exogenous PGE2, an effect that is prevented by ibuprofen (indicating a dependence upon endogenous PGE2). The involvement of Akt was indicated by the observation that 1) ONO-8711 and SC51089 increase Akt phosphorylation, and 2) MK2206, an Akt inhibitor, prevents the increased growth caused by ONO-8711. The involvement of the EGF receptor (EGFR) was indicated by 1) the increased phosphorylation of the EGFR caused by SC51089 and 2) the loss of the growth-stimulatory effect of ONO-8711 and SC51089 caused by the EGFR kinase inhibitor AG1478. The growth-stimulatory effect of ONO-8711 was lost following an EGFR knockdown, and transduction of MDCK cells with a dominant negative EGFR. These results support the hypothesis that 1) signaling via the EP1 receptor involves Akt as well as the EGFR, and 2), EP1 receptor pharmacology may be employed to prevent the aberrant growth associated with a number of renal diseases.
authors.affiliation: Biochemistry Department, University at Buffalo School of Medicine and Biomedical Sciences, Buffalo, New York biochtau@buffalo.edu.
authors.forename: Mary
authors.initials: M
authors.lastname: Taub
authors.affiliation: Biochemistry Department, University at Buffalo School of Medicine and Biomedical Sciences, Buffalo, New York.
authors.forename: Robert
authors.initials: R
authors.lastname: Parker
authors.affiliation: Biochemistry Department, University at Buffalo School of Medicine and Biomedical Sciences, Buffalo, New York.
authors.forename: Paremala
authors.initials: P
authors.lastname: Mathivanan
authors.affiliation: Biochemistry Department, University at Buffalo School of Medicine and Biomedical Sciences, Buffalo, New York.
authors.forename: Muhamad Asnawi Mohd
authors.initials: MA
authors.lastname: Ariff
authors.affiliation: Biochemistry Department, University at Buffalo School of Medicine and Biomedical Sciences, Buffalo, New York.
authors.forename: Trina
authors.initials: T
authors.lastname: Rudra
mesh_terms: D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology; D002208:Caproates / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology*; D004285:Dogs; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000502:physiology*; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006834:Hydrazines / Q000494:pharmacology; D007052:Ibuprofen / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000473:pathology* / Q000502:physiology; D061985:Madin Darby Canine Kidney Cells; D010077:Oxazepines / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000502:physiology*; D011799:Quinazolines / Q000494:pharmacology; D058306:Receptors, Prostaglandin E, EP1 Subtype / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000502:physiology; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000502:physiology; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D001643:Bridged Bicyclo Compounds; D002208:Caproates; D006575:Heterocyclic Compounds, 3-Ring; D006834:Hydrazines; C548887:MK 2206; C122148:ONO 8711; D010077:Oxazepines; D011799:Quinazolines; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D020032:Tyrphostins; C086836:SC 51089; C101044:RTKI cpd; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D007052:Ibuprofen
keywords: EP receptors; kidney epithelial cell growth; prostaglandin E2