Bcl-2 protects TK6 cells against hydroquinone-induced apoptosis through PARP-1 cytoplasm translocation and stabilizing mitochondrial membrane potential
Bcl-2 protects TK6 cells against hydroquinone-induced apoptosis through PARP-1 cytoplasm translocation and stabilizing mitochondrial membrane potential
复制标题
Bcl-2 通过 PARP-1 细胞质易位和稳定线粒体膜电位保护 TK6 细胞免受氢醌诱导的细胞凋亡
DOI：
10.1002/em.22126
复制
发表时间：
2018-01-01
影响因子：
2.8
通讯作者：
Tang, Huanwen
中科院分区：
文献类型：
--
作者：
Chen, Yuting;Chen, Shaoyun;Tang, Huanwen
B细胞白血病/淋巴瘤-2（Bcl-2）通过结合促凋亡因子的BH 3结构域并由此调节线粒体膜电位（MMP）来抑制凋亡。本研究旨在探讨Bcl-2在氢醌（HQ）诱导的TK 6细胞毒性过程中对线粒体凋亡途径的调控作用。苯的代谢产物HQ以浓度依赖性方式降低MMP，并诱导活性氧（ROS）的产生、DNA损伤标志物H2 AX的活化和DNA损伤响应酶聚（ADP-核糖）聚合酶-1（PARP-1）的产生。TK 6细胞暴露于HQ导致Bcl-2的增加以及与PARP-1在细胞质中的共定位。使用BH 3模拟物ABT-737抑制Bcl-2，抑制PARP-1核到细胞质的易位，并通过MMP的去极化使TK 6细胞对HQ诱导的凋亡敏感。Western blot分析表明，ABT-737与HQ组合增加了切割的PARP和-H2 AX的水平，但显著降低了P53的水平。因此，ABT-737可以影响PARP-1易位，并通过P53介导的凋亡途径诱导细胞凋亡。此外，我们发现PARP-1的敲低减弱了HQ诱导的切割的PARP和P53的产生。这些结果鉴定了Bcl-2作为HQ诱导的细胞凋亡的保护性介质，并显示Bcl-2的上调有助于将PARP-1定位于细胞质并稳定MMP。Environ.摩尔变异体59：49-59，2018. (c)2017 Wiley Periodicals，Inc.
B cell leukemia/lymphoma-2 (Bcl-2) suppresses apoptosis by binding the BH3 domain of proapoptotic factors and thereby regulating mitochondrial membrane potential (MMP). This study aimed to investigate the role of Bcl-2 in controlling the mitochondrial pathway of apoptosis during hydroquinone (HQ)-induced TK6 cytotoxicity. In this study, HQ, one metabolite of benzene, decreased the MMP in a concentration-dependent manner and induced the generation of reactive oxygen species (ROS), the activation of the DNA damage marker -H2AX, and production of the DNA damage-responsive enzyme poly(ADP-ribose)polymerase-1 (PARP-1). Exposure of TK6 cells to HQ leads to an increase in Bcl-2 and co-localization with PARP-1 in the cytoplasm. Inhibition of Bcl-2 using the BH3 mimetic, ABT-737, suppressed the PARP-1 nuclear to cytoplasm translocation and sensitized TK6 cells to HQ-induced apoptosis through depolarization of the MMP. Western blot analysis indicated that ABT-737 combined with HQ increased the levels of cleaved PARP and -H2AX, but significantly decreased the level of P53. Thus, ABT-737 can influence PARP-1 translocation and induce apoptosis via mitochondria-mediated apoptotic pathway, independently of P53. In addition, we found that knockdown of PARP-1 attenuated the HQ-induced production of cleaved PARP and P53. These results identify Bcl-2 as a protective mediator of HQ-induced apoptosis and show that upregulation of Bcl-2 helps to localize PARP-1 to the cytoplasm and stabilize MMP. Environ. Mol. Mutagen. 59:49-59, 2018. (c) 2017 Wiley Periodicals, Inc.