期刊
INTERNATIONAL JOURNAL OF ONCOLOGY
卷 42, 期 3, 页码 863-872出版社
SPANDIDOS PUBL LTD
DOI: 10.3892/ijo.2013.1769
关键词
hydrogen peroxide; tumor necrosis factor-related apoptosis-inducing ligand; melanoma; superoxide; apoptosis; endoplasmic reticulum
类别
资金
- Ministry of Education, Culture, Sports, Science and Technology (KAKENHI) [23591631]
- Nihon University
- Grants-in-Aid for Scientific Research [23591631] Funding Source: KAKEN
Intracellular reactive oxygen species (ROS) such as hydrogen peroxide (H2O2) are thought to mediate apoptosis induced by death receptor ligands, including tumornecrosis factor-related apoptosis-inducing ligand (TRAIL). However, the role of H2O2 is controversial, since some evidence suggests that H2O2 acts as an anti-apoptotic factor. Here, we show that exogenously applied H2O2 (30-100 JIM) induces cell death in TRAIL-resistant human melanoma cells via intracellular superoxide (O-2(-)) generation. H2O2 induced apoptotic or necrotic cell death, depending on the concentration of the oxidant applied; low concentrations of H2O2 preferentially activated the caspase-dependent apoptotic pathway, while high concentrations of H2O2 induced apoptotic and necrotic cell death in a caspase-independent manner. The H2O2-induced cell death was associated with increased mitochondrial membrane potential collapse and caspase-3/7 activation and ER stress responses including caspase-12 and X-box-binding protein-1 (XBP-1) activation. H2O2 induced intracellular O-2(-) generation even within the mitochondria, while TRAIL did not. The superoxide dismutase mimetic antioxidant MnTBaP [Mn (III) tetrakis (4-benzonic acid) porphyrin chloride] inhibited the H2O2-induced O-2(-) generation, apoptosis and XBP-1 and caspase-12 activation at comparable concentrations. Importantly, H2O2 treatment caused minimal O-2(-) generation and apoptosis in normal primary melanocytes. These data show that H2O2 induces endoplasmic reticulum-associated cell death via intracellular O-2(-) generation and that malignant melanoma cells are more susceptible than normal cells to this oxidative cell death. The findings suggest that H2O2 has therapeutic potential in the treatment of TRAIL-resistant melanoma.
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