Hydrogen peroxide induces cell death in human TRAIL-resistant melanoma through intracellular superoxide generation
Hydrogen peroxide induces cell death in human TRAIL-resistant melanoma through intracellular superoxide generation
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DOI：
10.3892/ijo.2013.1769
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发表时间：
2013-03-01
影响因子：
5.2
通讯作者：
Suzuki-Karasaki, Yoshihiro
中科院分区：
文献类型：
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作者：
Tochigi, Mizuki;Inoue, Toshio;Suzuki-Karasaki, Yoshihiro
细胞内活性氧（ROS）如过氧化氢（H2O2）被认为介导死亡受体配体诱导的细胞凋亡，包括肿瘤坏死因子相关细胞凋亡诱导配体（TRAIL）。然而，H2O2 的作用存在争议，因为一些证据表明 H2O2 具有抗凋亡因子的作用。在这里，我们发现外源施加的 H2O2 (30-100 JIM) 通过细胞内超氧化物 (O-2(-)) 的生成诱导 TRAIL 抗性人黑色素瘤细胞死亡。 H2O2 诱导细胞凋亡或坏死，具体取决于所用氧化剂的浓度；低浓度的H2O2优先激活caspase依赖的细胞凋亡途径，而高浓度的H2O2以不依赖caspase的方式诱导细胞凋亡和坏死。 H2O2 诱导的细胞死亡与线粒体膜电位塌陷和 caspase-3/7 激活以及 ER 应激反应（包括 caspase-12 和 X-box 结合蛋白-1 (XBP-1) 激活）增加有关。 H2O2 甚至在线粒体内也能诱导细胞内 O-2(-) 的产生，而 TRAIL 则不然。超氧化物歧化酶模拟抗氧化剂 MnTBaP [Mn (III) 四（4-苯甲酸）氯化卟啉] 在相当的浓度下抑制 H2O2 诱导的 O-2(-) 生成、细胞凋亡以及 XBP-1 和 caspase-12 激活。重要的是，H2O2 处理导致正常原代黑素细胞中 O-2(-) 的生成和细胞凋亡最少。这些数据表明，H2O2 通过细胞内 O-2(-) 的生成诱导内质网相关细胞死亡，并且恶性黑色素瘤细胞比正常细胞更容易受到这种氧化性细胞死亡的影响。研究结果表明，H2O2 在治疗 TRAIL 耐药性黑色素瘤方面具有治疗潜力。
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.