J7, a methyl jasmonate derivative, enhances TRAIL-mediated apoptosis through up-regulation of reactive oxygen species generation in human hepatoma HepG2 cells
J7, a methyl jasmonate derivative, enhances TRAIL-mediated apoptosis through up-regulation of reactive oxygen species generation in human hepatoma HepG2 cells
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DOI：
10.1016/j.tiv.2011.10.016
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发表时间：
2012-02-01
影响因子：
3.2
通讯作者：
Choi, Yung Hyun
中科院分区：
文献类型：
--
作者：
Park, Cheol;Jin, Cheng-Yun;Choi, Yung Hyun
肿瘤坏死因子 (TNF) 相关凋亡诱导配体 (TRAIL/APO2L) 是 TNF 基因超家族的成员，在与同源死亡受体结合后诱导细胞凋亡。虽然 TRAIL 对正常细胞相对无毒，但它选择性地诱导许多转化细胞凋亡。然而，一些人肝癌细胞对 TRAIL 的作用特别抵抗。在这项研究中，我们发现 J7（一种新型茉莉酸甲酯类似物）可使 TRAIL 耐药的 HepG2 人肝癌细胞对 TRAIL 介导的细胞凋亡敏感。我们的结果表明，与单独使用任一药物治疗相比，J7 显着增强 TRAIL 诱导的细胞凋亡。 J7 和 TRAIL 联合处理可有效诱导 Bid 裂解、XIAP、cIAP-1 和 Bcl-xL 下调、半胱天冬酶激活以及聚 (ADP-核糖) 聚合酶和磷脂酶 gamma-1 裂解。此外，暴露于 J7 后，细胞中活性氧 (ROS) 的产生显着增加，且呈时间依赖性。然而，J7 和 TRAIL 联合处理诱导的细胞毒性作用被 caspase 抑制剂显着减弱，表明 caspase 的重要作用。施用 ROS 清除剂 N-乙酰半胱氨酸也可显着抑制 J7 和 TRAIL 联合治疗诱导的细胞凋亡。这些结果支持 J7 联合 TRAIL 通过涉及 ROS 介导的 caspase 途径的信号级联诱导 HepG2 人肝癌细胞凋亡的机制。 (C) 2011 Elsevier Ltd. 保留所有权利。
The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL/APO2L), a member of the TNF gene superfamily, induces apoptosis upon engagement of cognate death receptors. While TRAIL is relatively non-toxic to normal cells, it selectively induces apoptosis in many transformed cells. Nevertheless, some human hepatoma cells are particularly resistant to the effects of TRAIL In this study, we show that J7, a novel methyl jasmonate analogue, sensitizes TRAIL-resistant HepG2 human hepatocarcinoma cells to TRAIL-mediated apoptosis. Our results indicate that J7 substantially enhances TRAIL-induced apoptosis, compared with treatment with either agent alone. Combined treatment with J7 and TRAIL effectively induced Bid cleavage, down-regulation of XIAP, cIAP-1 and Bcl-xL, activation of caspases, and cleavage of poly(ADP-ribose) polymerase and phopholipase gamma-1. In addition, generation of reactive oxygen species (ROS) showed a significant increase in cells following exposure to J7 in a time-dependent manner. However, the cytotoxic effects induced by co-treatment with J7 and TRAIL were markedly attenuated by caspase inhibitors, indicating an important role for caspases. Administration of N-acetyl cysteine, a scavenger of ROS, also resulted in significant inhibition of apoptosis induced by combinatory treatment with J7 and TRAIL These results support a mechanism whereby J7 plus TRAIL induces apoptosis of HepG2 human hepatoma cells through a signaling cascade involving a ROS-mediated caspase pathway. (C) 2011 Elsevier Ltd. All rights reserved.