title: Interplay between the prostaglandin transporter OATP2A1 and prostaglandin E2-mediated cellular effects.
abstract: Prostaglandins such as prostaglandin E2 (PGE2) play a pivotal role in physiological and pathophysiological pathways in gastric mucosa. Little is known about the interrelation of the prostaglandin E (EP) receptors with the prostaglandin transporter OATP2A1 in the gastric mucosa and gastric carcinoma. Therefore, we first investigated the expression of OATP2A1 and EP4 in normal and carcinoma gastric mucosa. Different PGE2-mediated cellular pathways and mechanisms were investigated using human embryonic kidney cells (HEK293) and the human gastric carcinoma cell line AGS stably transfected with OATP2A1. Colocalization and expression of OATP2A1 and EP4 were detected in mucosa of normal gastric tissue and of gastric carcinomas. OATP2A1 reduced the PGE2-mediated cAMP production in HEK293 and AGS cells overexpressing EP4 and OATP2A1. The expression of OATP2A1 in AGS cells resulted in a reduction of [(3)H]-thymidine incorporation which was in line with a higher accumulation of AGS-OATP2A1 cells in S-phase of the cell cycle compared to control cells. In contrast, the expression of OATP2A1 in HEK293 cells had no influence on the distribution in the S-phase compared to control cells. OATP2A1 also diminished the PGE2-mediated expression of interleukin-8 mRNA (IL-8) and hypoxia-inducible-factor 1α (HIF1α) protein in AGS-OATP2A1 cells. The expression of OATP2A1 increased the sensitivity of AGS cells against irinotecan which led to reduced cell viability. Taken together, these data show that OATP2A1 influences PGE2-mediated cellular pathways. Therefore, OATP2A1 needs to be considered as a key determinant for the understanding of the physiology and pathophysiology of prostaglandins in healthy and tumorous gastric mucosa.
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Fahrstraße 17, 91054 Erlangen, Germany. Electronic address: krystyna.bujok@fau.de.
authors.forename: Krystyna
authors.initials: K
authors.lastname: Bujok
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Fahrstraße 17, 91054 Erlangen, Germany. Electronic address: hartmut.glaeser@fau.de.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Glaeser
authors.affiliation: Division of Molecular Immunology, Nikolaus Fiebiger Center, Department of Internal Medicine III, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Glückstraße 6, 91054 Erlangen, Germany. Electronic address: wschuh@molmed.uni-erlangen.de.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Schuh
authors.affiliation: Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Krankenhausstraße 8-10, 91054 Erlangen, Germany; Institute of Pathology, University of Bern, Murtenstrasse 31, 3010 Bern, Switzerland. Electronic address: Tilman.Rau@pathology.unibe.ch.
authors.forename: Tilman T
authors.initials: TT
authors.lastname: Rau
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Fahrstraße 17, 91054 Erlangen, Germany. Electronic address: ingrid.schmidt@fau.de.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Schmidt
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Fahrstraße 17, 91054 Erlangen, Germany. Electronic address: martin.fromm@fau.de.
authors.forename: Martin F
authors.initials: MF
authors.lastname: Fromm
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Fahrstraße 17, 91054 Erlangen, Germany. Electronic address: kathrin.mandery@fau.de.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Mandery
mesh_terms: D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D015232:Dinoprostone / Q000494:pharmacology*; D005753:Gastric Mucosa / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007150:Immunohistochemistry; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D000077146:Irinotecan; D027361:Organic Anion Transporters / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000235:genetics / Q000378:metabolism; D059807:S Phase Cell Cycle Checkpoints / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016209:Interleukin-8; D027361:Organic Anion Transporters; D012333:RNA, Messenger; D058309:Receptors, Prostaglandin E, EP4 Subtype; C503526:SLCO2A1 protein, human; D000077146:Irinotecan; D000242:Cyclic AMP; D015232:Dinoprostone; D002166:Camptothecin
keywords: Cellular signaling; EP4; OATP2A1; Prostaglandin E(2); Prostaglandin transporter; cAMP