title: Involvement of mitogen-activated protein kinases and protein kinase C in cadmium-induced prostaglandin E2 production in primary mouse osteoblastic cells.
abstract: We previously reported that cadmium (Cd) induced prostaglandin E2 (PGE2) biosynthesis through the activation of cytosolic phospholipase A2 (cPLA2) and induction of cyclooxygenase 2 (COX-2) in primary mouse osteoblastic cells. In the present study, we further investigated the mechanism of PGE2 production by Cd focusing on the main mitogen-activated protein kinase (MAPK) subfamilies that mediate prostaglandin synthesis, extracellular signal-regulated kinase (ERK1/2 MAPK), c-jun-amino-terminal kinase (JNK MAPK) and p38 MAPK, and protein kinase C (PKC) which is activated by Cd in several kinds of cells. Cd at 2 microM and above stimulated PGE2 production in osteoblastic cells and its production was inhibited by the kinase-specific inhibitors PD98059, SB203580, curcumin, and calphostin C. Calphostin C also inhibited the production of PGE2 by phorbol 12-myristate 13-acetate (PMA), which is a potent activator of PKC. PD98059 inhibited PGE2 production stimulated by PMA as well as Cd, indicating that activation of PKC by ERK1/2 MAPK was necessary for Cd-stimulated PGE2 production. Moreover, Cd stimulated the phosphorylation of these three MAPKs, and inhibition of the phosphorylation of ERK1/2 MAPK by calphostin C was also observed. On the other hand, Cd was found to phosphorylate cPLA2 and the phosphorylation was inhibited by PD98059, indicating that cPLA2 was activated by Cd through ERK1/2 MAPK and released arachidonic acid (AA), a substrate of COX-2, from membranous phospholipids. From these results, it was suggested that activation of each of the ERK1/2, p38, and JNK MAPK cascades in addition to that of PKC and cPLA2 played an important role in the Cd-stimulated biosynthesis of PGE2 in mouse osteoblastic cells.
authors.affiliation: Department of Toxicology, Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama-shi, 930-0194, Japan. tmiya@ms.toyama-mpu.ac.jp
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Miyahara
authors.forename: Terutaka
authors.initials: T
authors.lastname: Katoh
authors.forename: Makoto
authors.initials: M
authors.lastname: Watanabe
authors.forename: Yasutaro
authors.initials: Y
authors.lastname: Mikami
authors.forename: Saki
authors.initials: S
authors.lastname: Uchida
authors.forename: Miwa
authors.initials: M
authors.lastname: Hosoe
authors.forename: Tutomu
authors.initials: T
authors.lastname: Sakuma
authors.forename: Nobuo
authors.initials: N
authors.lastname: Nemoto
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Takayama
authors.forename: Toshi
authors.initials: T
authors.lastname: Komurasaki
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002104:Cadmium / Q000633:toxicity*; D015232:Dinoprostone / Q000096:biosynthesis*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007700:Kinetics; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009281:Naphthalenes / Q000494:pharmacology; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism*; D010741:Phospholipases A / Q000378:metabolism; D054467:Phospholipases A2; D010766:Phosphorylation; D011247:Pregnancy; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D009281:Naphthalenes; D011725:Pyridines; D002104:Cadmium; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D010741:Phospholipases A; D054467:Phospholipases A2; C058819:calphostin C; D015232:Dinoprostone; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one