title: Mitochondrial superoxide mediates mitochondrial and endoplasmic reticulum dysfunctions in TRAIL-induced apoptosis in Jurkat cells.
abstract: Reactive oxygen species (ROS), such as superoxide (O2(•-)) and hydrogen peroxide (H2O2), have been reported to be important mediators of the apoptosis induced by death ligands, including Fas, tumor necrosis factor-α, and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Conversely, there is evidence that H2O2 and prooxidative conditions are protective. Therefore, the roles of ROS in death ligand-induced apoptosis are a matter of debate. In this study, we attempted to define the oxidant species mediating TRAIL-induced apoptosis in human tumor cells. The generation of intracellular O2(•-), but not H2O2, was correlated with apoptosis in the cells. TRAIL treatment resulted in increased mitochondrial O2(•-) generation and the oxidation of cardiolipin. The O2(•-)-selective scavenger MnTBaP [Mn(III) tetrakis (4-benzoic acid) porphyrin chloride] specifically blocked TRAIL-induced apoptosis and proapoptotic events including mitochondrial membrane collapse and caspase-3/7 activation. TRAIL also induced endoplasmic reticulum (ER) stress responses including caspase-12 activation, while inhibition of caspase-12 prevented the apoptosis. In addition, increased mitochondrial O2(•-) generation by uncoupling of oxidative phosphorylation or inhibition of the electron transport chain amplified the TRAIL-induced apoptosis and proapoptotic events. This amplification was also significantly abolished by MnTBaP treatment. Our data indicate that mitochondrial O2(•-) mediates mitochondrial and ER dysfunctions during TRAIL-induced apoptosis in Jurkat cells. The present findings suggest that pharmacological agents increasing mitochondrial O2(•-) may serve as clinical drugs that amplify TRAIL effectiveness toward cancer cells.
authors.affiliation: Division of Molecular Cell Immunology and Allergology, Department of Biomedical Sciences, Nihon University School of Medicine, Tokyo, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Inoue
authors.affiliation: Division of Molecular Cell Immunology and Allergology, Department of Biomedical Sciences, Nihon University School of Medicine, Tokyo, Japan; Division of Physiology, Department of Biomedical Sciences, Nihon University School of Medicine, Tokyo, Japan; Innovative Therapy Research Group, Nihon University Research Institute of Medical Science, Tokyo, Japan. Electronic address: suzuki.yoshihiro@nihon-u.ac.jp.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Suzuki-Karasaki
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D053454:Caspase 12 / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000502:physiology*; D059865:Endoplasmic Reticulum Stress; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D019169:Jurkat Cells; D008928:Mitochondria / Q000502:physiology*; D013481:Superoxides / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*
chemical_list: D053221:TNF-Related Apoptosis-Inducing Ligand; D013481:Superoxides; D006861:Hydrogen Peroxide; D053454:Caspase 12
keywords: Apoptosis; Endoplasmic reticulum; Mitochondria; ROS; Superoxide; Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)