マツザワ　ヤスオ   Matsuzawa Yasuo   松澤　康雄    所属   東邦大学  医学部 医学科（佐倉病院）    職種   臨床教授
論文種別	原著
言語種別	英語
査読の有無	査読あり
表題	Cytotoxicity induced by inhibition of thioredoxin reductases via multiple signaling pathways: Role of cytosolic phospholipase A2-dependent and -independent release of arachidonic acid
掲載誌名	正式名：Journal of Cellular Physiology 略　 称：J Cell Physiol.
巻・号・頁	219(3),pp.606-616
著者・共著者	Kurosawa T, Nakamura N, Yamaura E, Fujino H, Matsuzawa Y†, Kawashima T†, Murayama T
発行年月	2009/01
概要	The thioredoxin (Trx) system, comprising Trx, the selenoprotein thioredoxin reductase (TrxR), and NADPH, functions as an antioxidant system. Trx has various biological activities including growth control and anti-apoptotic properties, and the Trx system offers a target for the development of drugs to treat and/or prevent cancer. We evaluated the role of TrxR inhibition in the release of arachidonic acid (AA), cell toxicity, and intracellular signaling pathways in L929 mouse fibrosarcoma cells. Treatment with 1-chloro-2,4-dinitrobenzene (DNCB, an inhibitor of TrxR) under conditions involving limited inhibition of TrxR activity in cells, released AA before causing cytotoxicity. Treatment with an inhibitor of p38 kinase, a downstream enzyme of the apoptosis signal-regulating kinase 1 pathway, and pyrrophenone (an inhibitor of -type cytosolic phospholipase A2, cPLA2) partially but significantly decreased the DNCB-induced release of AA and cell death. The responses were much weaker in cPLA2 knockdown L929 cells. Exogenously added AA showed cytotoxicity. DNCB increased intracellular reactive oxygen species (ROS) levels, and butylated hydroxyanisole (an antioxidant) reduced DNCB-induced ROS formation and cell toxicity but not the phosphorylation of p38 kinase and release of AA. Auranofin, another inhibitor of TrxR having a different formula, released AA resulting in toxicity in L929 cells. DNCB caused the release of AA and cytotoxicity in A549 human lung carcinoma cells, and caused p38 kinase-dependent toxicity in PC12 rat pheochromocytoma cells. Our data suggest that a dysfunctional Trx system triggers multiple signaling pathways, and that the AA released by cPLA2-dependent and -independent pathways is important to cytotoxicity