title: Diarachidonoylphosphoethanolamine induces necrosis/necroptosis of malignant pleural mesothelioma cells.
abstract: The present study investigated 1,2-diarachidonoyl-sn-glycero-3-phosphoethanolamine (DAPE)-induced cell death in malignant pleural mesothelioma (MPM) cells. DAPE reduced cell viability in NCI-H28, NCI-H2052, NCI-H2452, and MSTO-211H MPM cell lines in a concentration (1-100μM)-dependent manner. In the flow cytometry using propidium iodide (PI) and annexin V (AV), DAPE significantly increased the population of PI-positive and AV-negative cells, corresponding to primary necrosis, and that of PI-positive and AV-positive cells, corresponding to late apoptosis/secondary necrosis, in NCI-H28 cells. DAPE-induced reduction of NCI-H28 cell viability was partially inhibited by necrostatin-1, an inhibitor of RIP1 kinase to induce necroptosis, or knocking-down RIP1. DAPE generated reactive oxygen species (ROS) followed by disruption of mitochondrial membrane potentials in NCI-H28 cells. DAPE-induced mitochondrial damage was attenuated by cyclosporin A, an inhibitor of cyclophilin D (CypD). DAPE did not affect expression and mitochondrial localization of p53 protein in NCI-H28 cells. DAPE significantly decreased intracellular ATP concentrations in NCI-H28 cells. Overall, the results of the present study indicate that DAPE induces necroptosis and necrosis of MPM cells; the former is mediated by RIP1 kinase and the latter is caused by generating ROS and opening CypD-dependent mitochondrial permeability transition pore, to reduce intracellular ATP concentrations.
authors.affiliation: Division of Bioinformation, Department of Physiology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya 663-8501, Japan.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Kaku
authors.affiliation: Division of Bioinformation, Department of Physiology, Hyogo College of Medicine, 1-1 Mukogawa-cho, 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, 1-1 Mukogawa-cho, Nishinomiya 663-8501, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kanno
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, 1-1 Mukogawa-cho, Nishinomiya 663-8501, Japan. Electronic address: tomoyuki@hyo-med.ac.jp.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Nishizaki
mesh_terms: D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D008654:Mesothelioma / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D009336:Necrosis / Q000188:drug therapy; D009363:Neoplasm Proteins / Q000378:metabolism*; D010714:Phosphatidylethanolamines / Q000494:pharmacology*; D010997:Pleural Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology
chemical_list: D009363:Neoplasm Proteins; D010714:Phosphatidylethanolamines; C044820:1,2-diarachidonoyl-glycero-3-phosphoethanolamine
keywords: Diarachidonoylphosphoethanolamine; Malignant pleural mesothelioma cell; Mitochondria; Necroptosis; Necrosis