Oxidative stress initiates DNA damager MNNG-induced poly(ADP-ribose)polymerase-1-dependent parthanatos cell death
Oxidative stress initiates DNA damager MNNG-induced poly(ADP-ribose)polymerase-1-dependent parthanatos cell death
复制标题
DOI：
10.1016/j.bcp.2010.10.016
复制
发表时间：
2011-02-01
影响因子：
5.8
通讯作者：
Lin, Wan-Wan
中科院分区：
文献类型：
--
作者：
Chiu, Ling-Ya;Ho, Feng-Ming;Lin, Wan-Wan
烷基化剂n -甲基-n '-硝基-n '-亚硝基胍（MNNG）可引起过量的DNA链断裂，导致聚（adp -核糖）聚合酶-1 （PARP-1）过度激活和细胞死亡（parthanatos）。然而，对mnng诱导的parthanatos的具体机制尚未深入研究。在这项研究中，我们使用mnng处理的小鼠胚胎成纤维细胞（mef）来阐明mnng诱导的旁咽喉炎的信号通路。我们发现mnng诱导的细胞死亡伴随着PARP-1的快速激活、c-Jun n -末端激酶（JNK）的激活、双相活性氧（ROS）的产生和细胞内钙的增加。在MNNG处理后的第1分钟和第5-15分钟达到峰值，部分原因是NADPH氧化酶的作用。相比之下，线粒体在MNNG处理后30分钟产生后期ROS，并在6小时内产生时间依赖性增加。抗氧化剂NAC可以消除MNNG引起的所有现象。结果表明，钙升高是早期ROS产生的下游，并参与PARP-1和JNK的激活。此外，PARP抑制剂能够减少mnng诱导的晚期ROS生成、钙升高和细胞死亡。结果进一步表明RIP1参与持续的ROS生成和钙的增加。我们表征了ROS、钙、JNK和RIP1在mnng诱导的细胞死亡中的相互作用。我们发现，除了先前证明的烷基化特性外，MNNG引发的ROS产生还会导致DNA损伤和PARP-1活化的增强。此外，细胞内钙的升高和ROS的产生具有相互放大的作用，从而促进parp -1介导的parthanatos。(C) 2010爱思唯尔公司版权所有。
The alkylating agent N-methyl-N'-nitro-N'-nitrosoguanidine (MNNG) can cause excess DNA strand breaks that lead to poly(ADP-ribose)polymerase-1 (PARP-1) overactivation and cell death (parthanatos). However, the detail mechanism of MNNG-induced parthanatos was not well-investigated. In this study, we used MNNG-treated mouse embryonic fibroblasts (MEFs) to elucidate the signaling pathways of MNNG-induced parthanatos. We found that MNNG-induced cell death accompanied by rapid PARP-1 activation, c-Jun N-terminal kinase (JNK) activation, biphasic reactive oxygen species (ROS) production and intracellular calcium increase. The early ROS production occurring at 1 min and peaking at 5-15 min after MNNG treatment partially resulted from NADPH oxidase. In contrast, the late phase of ROS production occurring at 30 min and time-dependently increasing up to 6 h after MNNG treatment was generated by mitochondria. The antioxidant, NAC can abrogate all phenomena caused by MNNG. Results indicate that the calcium rise was downstream of early ROS production, and was involved in PARP-1 and JNK activation. Moreover, the PARP inhibitor was able to reduce MNNG-induced late-phase ROS production, calcium elevation, and cell death. Results further indicated the involvement of RIP1 in sustained ROS production and calcium increase. We characterized the interactive roles of ROS, calcium, JNK, and RIP1 in MNNG-induced cell death. We found that in addition to the alkylating property previously demonstrated, ROS production triggered by MNNG results in enhanced DNA damage and PARP-1 activation. Moreover, intracellular calcium elevation and ROS production have mutual amplification effects and thus contribute to PARP-1-mediated parthanatos. (C) 2010 Elsevier Inc. All rights reserved.