title: 15-Deoxy-Δ12,14-prostaglandin J2 induces Cox-2 expression in human osteosarcoma cells through MAPK and EGFR activation involving reactive oxygen species.
abstract: Prostaglandins (PGs), important modulators in bone biology, may also contribute to tumor formation and progression in human osteosarcoma. 15-Deoxy-Δ(12,14)-PGJ(2) (15d-PGJ(2)), a metabolite of PGD(2) and PPARγ-ligand, exerts a panel of biological activities via receptor-dependent and -independent mechanisms. As inducible cyclooxygenase-2 (Cox-2) is a candidate inflammatory marker in human osteosarcoma and a rate-limiting enzyme in PG biosynthesis, this study aimed at investigating intracellular redox status and signaling cascades leading to Cox-2 induction in human MG-63 osteosarcoma cells. 15d-PGJ(2) induced the accumulation of reactive oxygen species (ROS) that in turn may lead to upregulation of Cox-2 via two different routes in a PPARγ-independent manner. First, phosphorylation of p38 MAPK directly enhances Cox-2 expression by promoting mRNA stability. Second, 15d-PGJ(2) induces activation of epidermal growth factor receptors and downstream activation of Cox-2 via phosphorylation of p42/44 MAPK. Glutathione precursor molecules reversed enhanced ROS levels and Cox-2 expression. Functional activity of Cox-2 expression was tested by measurement of PGE(2) and PGF(2α). The synthetic compound 9,10-dihydro-15d-PGJ(2) lacking the α,β-unsaturated carbonyl group in the cyclopentenone ring did not exhibit the cellular responses observed with 15d-PGJ(2). We conclude that the electrophilic carbon atom of 15d-PGJ(2) is responsible for alterations in intracellular redox status and Cox-2 expression.
authors.affiliation: Department of Pediatrics and Adolescence Medicine, Research Unit of Osteological Research and Analytical Mass Spectrometry, Medical University of Graz, A-8036 Graz, Austria.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Kitz
authors.forename: Werner
authors.initials: W
authors.lastname: Windischhofer
authors.forename: Hans-Jörg
authors.initials: HJ
authors.lastname: Leis
authors.forename: Evelyn
authors.initials: E
authors.lastname: Huber
authors.forename: Manfred
authors.initials: M
authors.lastname: Kollroser
authors.forename: Ernst
authors.initials: E
authors.lastname: Malle
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D015237:Dinoprost / Q000032:analysis / Q000096:biosynthesis; D015232:Dinoprostone / Q000032:analysis / Q000096:biosynthesis; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D020871:RNA Stability / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; C037112:9-deoxy-delta-9-prostaglandin D2; D015237:Dinoprost; D051546:Cyclooxygenase 2; C512478:EGFR protein, human; D066246:ErbB Receptors; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D005978:Glutathione; D015232:Dinoprostone; D015230:Prostaglandin D2