Mitochondrial superoxide mediates mitochondrial and endoplasmic reticulum dysfunctions in TRAIL-induced apoptosis in Jurkat cells.
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.
['Inoue|Toshio|T|', 'Suzuki-Karasaki|Yoshihiro|Y|']
D017209:Apoptosis D053454:Caspase 12 D004721:Endoplasmic Reticulum D059865:Endoplasmic Reticulum Stress D006801:Humans D006861:Hydrogen Peroxide D019169:Jurkat Cells D008928:Mitochondria D013481:Superoxides D053221:TNF-Related Apoptosis-Inducing Ligand
Superoxide Endoplasmic reticulum Apoptosis ROS Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) Mitochondria