title: Diarachidonoylphosphoethanolamine induces apoptosis of malignant pleural mesothelioma cells through a Trx/ASK1/p38 MAPK pathway.
abstract: 1,2-Diarachidonoyl-sn-glycero-3-phosphoethanolamine (DAPE) induces both necrosis/necroptosis and apoptosis of NCI-H28 malignant pleural mesothelioma (MPM) cells. The present study was conducted to understand the mechanism for DAPE-induced apoptosis of NCI-H28 cells. DAPE induced caspase-independent apoptosis of NCI-H28 malignant pleural mesothelioma (MPM) cells, and the effect of DAPE was prevented by antioxidants or an inhibitor of NADPH oxidase (NOX). DAPE generated reactive oxygen species (ROS) and inhibited activity of thioredoxin (Trx) reductase (TrxR). DAPE decreased an association of apoptosis signal-regulating kinase 1 (ASK1) with thioredoxin (Trx), thereby releasing ASK1. DAPE activated p38 mitogen-activated protein kinase (MAPK), which was inhibited by an antioxidant or knocking-down ASK1. In addition, DAPE-induced NCI-H28 cell death was also prevented by knocking-down ASK1. Taken together, the results of the present study indicate that DAPE stimulates NOX-mediated ROS production and suppresses TrxR activity, resulting in the decrease of reduced Trx and the dissociation of ASK1 from a complex with Trx, allowing sequential activation of ASK1 and p38 MAPK, to induce apoptosis of NCI-H28 MPM cells.
authors.affiliation: Division of Bioinformation, Department of Physiology, Hyogo College of Medicine, Nishinomiya 663-8501, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Tsuchiya
authors.affiliation: Division of Bioinformation, Department of Physiology, Hyogo College of Medicine, Nishinomiya 663-8501, Japan.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Kaku
authors.affiliation: Division of Respiratory Medicine, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya 663-8501, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakano
authors.affiliation: Division of Bioinformation, Department of Physiology, Hyogo College of Medicine, Nishinomiya 663-8501, Japan. Electronic address: tomoyuki@hyo-med.ac.jp.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Nishizaki
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology*; D008654:Mesothelioma / Q000473:pathology*; D000086002:Mesothelioma, Malignant; D019255:NADPH Oxidases / Q000378:metabolism; D010714:Phosphatidylethanolamines / Q000494:pharmacology*; D010997:Pleural Neoplasms / Q000473:pathology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013879:Thioredoxins / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D010714:Phosphatidylethanolamines; D017382:Reactive Oxygen Species; C491203:TXN protein, human; D013879:Thioredoxins; C044820:1,2-diarachidonoyl-glycero-3-phosphoethanolamine; D019255:NADPH Oxidases; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; C482858:MAP3K5 protein, human
keywords: 1,2-Diarachidonoyl-sn-glycero-3-phosphoethanolamine; Apoptosis signal-regulating kinase 1; Reactive oxygen species; Thioredoxin; p38 Mitogen-activated protein kinase