title: Intracellular prostaglandin E2 mediates cisplatin-induced proximal tubular cell death.
abstract: Nephrotoxicity, particularly in the proximal tubule, limits the therapeutic efficacy of the antineoplastic drug cisplatin. The signaling mechanisms appear to be multifactorial, involving inflammation, oxidative stress, and caspase. Here we studied the role of intracellular prostaglandin E2 (iPGE2) in cisplatin's cytotoxicity in human proximal tubular HK-2 cells. Cisplatin-induced apoptotic cell death was prevented by inhibitors of the prostaglandin transporter (PGT) or by PGT knock-down or by pharmacologic inhibition of PGE2 EP receptors or cyclo-oxygenase-2 (COX-2). iPGE2 also increased in cisplatin-treated cells, which was probably due to increased expression of COX-2, microsomal PGE2 synthase-1 and PGT, and was prevented by inhibitors of PGT or COX-2. Thus iPGE2, most likely acting through intracellular EP receptors, mediates cisplatin-induced HK-2 cell death. Importantly, the tumoricidal effect of cisplatin on human cervical adenocarcinoma HeLa cells was not affected by a pharmacologic inhibitor of PGT. In conclusion, iPGE2 may play a significant role in the pathogenesis of cisplatin’s nephrotoxicity and treatment with PGT inhibitors might represent a novel strategy in its prevention.
authors.affiliation: Departamento de Biología, Universidad Autónoma de Madrid, Madrid, Spain. Electronic address: anab.fernandez@uam.es.
authors.forename: Ana B
authors.initials: AB
authors.lastname: Fernández-Martínez
authors.affiliation: Departamento de Biología de Sistemas, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain.
authors.forename: Selma
authors.initials: S
authors.lastname: Benito Martínez
authors.affiliation: Departamento de Biología de Sistemas, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Lucio Cazaña
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018613:Microscopy, Confocal; D027361:Organic Anion Transporters / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000970:Antineoplastic Agents; D027361:Organic Anion Transporters; D018078:Receptors, Prostaglandin E; C503526:SLCO2A1 protein, human; D051546:Cyclooxygenase 2; D015232:Dinoprostone; D002945:Cisplatin