Caspase-independent cell death by arsenic trioxide in human cervical cancer cells: Reactive oxygen species-mediated poly(ADP-ribose) polymerise-1 activation signals apoptosis-inducing factor release from mitochondria
Caspase-independent cell death by arsenic trioxide in human cervical cancer cells: Reactive oxygen species-mediated poly(ADP-ribose) polymerise-1 activation signals apoptosis-inducing factor release from mitochondria
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DOI：
10.1158/0008-5472.can-04-1830
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发表时间：
2004-12-15
期刊：
影响因子：
11.2
通讯作者：
Lee, SJ
中科院分区：
文献类型：
--
作者：
Kang, YH;Yi, MJ;Lee, SJ
虽然三氧化二砷（As 2 O3）诱导的细胞死亡的机制已被广泛研究，在血液系统癌症，那些在实体肿瘤尚未明确界定。在这项研究中，我们发现，易位的凋亡诱导因子（AIF）从线粒体到细胞核所需的As 2 O3诱导的人宫颈癌细胞的细胞死亡。我们还发现，活性氧（ROS）介导的聚（ADP-核糖）聚合酶-1（PARP-1）激活是必要的AIF从线粒体释放。用As 2 O3处理人宫颈癌细胞诱导线粒体膜电位（Deltapsi（m））的耗散、AIF从线粒体易位到细胞核以及随后的细胞死亡。靶向AIF的小干扰RNA有效地保护宫颈癌细胞免受As 2 O3诱导的细胞死亡。As_2O_3还诱导细胞内ROS水平升高和PARP-1的显著激活。N-乙酰基-L-半胱氨酸是一种含巯基的抗氧化剂，可完全阻断As 2 O3诱导的PARP-1活化、Deltapsi（m）丢失、AIF从线粒体核转位以及随后的细胞死亡。此外，1，5-二羟基异喹啉或3，4-二氢-5-[4-（1-哌啶基）丁氧基]-1（2 H）-异喹啉酮（PARP-1抑制剂）的预处理有效地减弱了Deltapsi（m）的损失、AIF释放和细胞死亡。这些数据支持ROS介导的PARP-1激活信号AIF从线粒体释放的概念，导致As 2 O3处理实体瘤细胞中细胞死亡的半胱天冬酶非依赖性途径的激活。
Although mechanisms of arsenic trioxide (As2O3)-induced cell death have been studied extensively in hematologic cancers, those in solid cancers have yet to be clearly defined. In this study, we showed that the translocation of apoptosis-inducing factor (AIF) from mitochondria to the nucleus is required for As2O3-induced cell death in human cervical cancer cells. We also showed that reactive oxygen species (ROS)-mediated poly(ADP-ribose) polymerise-1 (PARP-1) activation is necessary for AIF release from mitochondria. The treatment of human cervical cancer cells with As2O3 induces dissipation of mitochondrial membrane potential (Deltapsi(m)), translocation of AIF from mitochondria to the nucleus, and subsequent cell death. Small interfering RNA targeting of AIF effectively protects cervical cancer cells against As2O3 induced cell death. As2O3 also induces an increase of intracellular ROS level and a marked activation of PARP-1. N-acetyl-L-cystein, a thiol-containing antioxidant, completely blocks As2O3-induced PARP-1 activation, Deltapsi(m) loss, nuclear translocation of AIF from mitochondria, and the consequent cell death. Furthermore, pretreatment of 1,5-dihydroxyisoquinoline or 3,4-dihydro-5-[4-(1-piperidinyl)butoxyl-1(2H)-isoquinolinone, PARP-1 inhibitors, effectively attenuates the loss of Deltapsi(m), AIF release, and cell death. These data support a notion that ROS-mediated PARP-1 activation signals AIF release from mitochondria, resulting in activation of a caspase-independent pathway of cell death in solid tumor cells by As2O3 treatment.