GL-V9 induced upregulation and mitochondrial localization of NAG-1 associates with ROS generation and cell death in hepatocellular carcinoma cells
GL-V9 induced upregulation and mitochondrial localization of NAG-1 associates with ROS generation and cell death in hepatocellular carcinoma cells
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GL-V9 诱导 NAG-1 的上调和线粒体定位与肝细胞癌细胞中 ROS 的产生和细胞死亡相关
DOI：
10.1016/j.freeradbiomed.2017.07.011
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发表时间：
2017
影响因子：
7.4
通讯作者：
Zhao Li
中科院分区：
文献类型：
--
作者：
Zhang Xiaobo;Kang Yue;Huo Tongxin;Tao Ran;Wang Xiaoping;Li Zhiyu;Guo Qinglong;Zhao Li
我们以前曾报道过一种新合成的化合物GL-V9可以诱导线粒体介导的HepG2细胞凋亡。然而，其潜在的机制还没有完全被理解。在目前的研究中，我们进一步表明GL-V9对几种肝癌细胞株的生长具有显著的抑制作用。此外，GL-V9诱导的生长抑制与与肿瘤抑制相关的转化生长因子β超家族成员非类固醇抗炎药激活基因-1(NAG-1)的强烈上调是一致的。进一步分析发现，GL-V9激活的p38MAPK通路有助于提高NAG-1mRNA的稳定性。有趣的是，我们观察到GL-V9诱导的细胞内NAG-1蛋白至少部分地定位于线粒体，在那里它可能影响蛋白的表达，从而导致线粒体膜电位(MMP)的耗散和线粒体超氧化物的积累，最终促进细胞凋亡。沉默NAG-1可减轻GL-V9诱导的线粒体相关细胞凋亡。此外，GL-V9还抑制了移植瘤模型中肿瘤的生长，并上调了肿瘤组织中NAG-1的表达。综上所述，这些数据表明NAG-1可能在GL-V9引发的线粒体凋亡中发挥重要作用，从而为GL-V9作为抗人肝癌化疗药物提供了新的机制解释和潜在的靶点。
We have previously reported that a newly synthesized compound, GL-V9 could induce mitochondria-mediated apoptosis in HepG2 cells. However, the underlying mechanisms have not been fully understood yet. In current study, we further showed that GL-V9 exhibited significant inhibitory effect on growth of several hepatocellular carcinoma cell lines. Moreover, GL-V9-induced growth inhibition was coincident with the strong upregulation of nonsteroidal anti-inflammatory drug-activated gene-1 (NAG-1), a TGFβ superfamily member, which has been linked with tumor suppression. Further analysis uncovered that GL-V9-activated p38 MAPK pathway contributed to enhancement of NAG-1 mRNA stability. Interestingly, we observed that the intracellular NAG-1 protein induced by GL-V9 could, at least in part, localize in mitochondria where it might affect protein expression, thereby resulting in dissipation of mitochondria membrane potential (MMP) and accumulation of mitochondrial superoxide, eventually facilitating to apoptosis events. Silence of NAG-1 could attenuate mitochondria related apoptosis caused by GL-V9. Moreover, GL-V9 suppressed tumor growth in xenograft model accompanied with upregulation of NAG-1 in tumor tissues. Collectively, these data demonstrated that NAG-1 could play an important role in mitochondria apoptosis triggered by GL-V9, thus providing novel mechanistic explanations and potential target for using GL-V9 as a chemotherapeutic agent against human hepatocellular carcinoma.