Marine Streptomyces sp. derived antimycin analogues suppress HeLa cells via depletion HPV E6/E7 mediated by ROS-dependent ubiquitin-proteasome system.
Marine Streptomyces sp. derived antimycin analogues suppress HeLa cells via depletion HPV E6/E7 mediated by ROS-dependent ubiquitin-proteasome system.
复制标题
海洋链霉菌衍生的抗霉素类似物通过 ROS 依赖性泛素蛋白酶体系统介导的 HPV E6/E7 消耗抑制 HeLa 细胞
DOI：
10.1038/srep42180
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发表时间：
2017-02-08
影响因子：
4.6
通讯作者：
Liu M
中科院分区：
文献类型：
--
作者：
Zhang W;Che Q;Tan H;Qi X;Li J;Li D;Gu Q;Zhu T;Liu M
从海洋链霉菌THS-55的培养物中分离得到4个新的抗霉素生物碱（1-4）和6个已知类似物（5-10），通过光谱分析鉴定了它们的结构。所有化合物在体外对HPV转化的HeLa细胞系表现出强的细胞毒性。其中化合物6-7为首次从天然产物中得到，化合物5（NADA）的活性最高。NADA可抑制HeLa细胞的增殖，阻滞细胞周期分布，并引发细胞凋亡。我们的分子力学研究表明，NADA通过ROS介导的泛素依赖性蛋白酶体系统激活来降解E6/E7癌蛋白的水平。这是第一份证明抗霉素生物碱类似物诱导高危HPV E6/E7癌蛋白降解并最终诱导宫颈癌细胞凋亡的报告。目前的工作表明，这些类似物可以作为开发HPV感染的宫颈癌治疗药物的先导化合物，以及E6/E7功能研究的研究工具。
Four new antimycin alkaloids (1–4) and six related known analogs (5–10) were isolated from the culture of a marine derived Streptomyces sp. THS-55, and their structures were elucidated by extensive spectroscopic analysis. All of the compounds exhibited potent cytotoxicity in vitro against HPV-transformed HeLa cell line. Among them, compounds 6–7 were derived as natural products for the first time, and compound 5 (NADA) showed the highest potency. NADA inhibited the proliferation, arrested cell cycle distribution, and triggered apoptosis in HeLa cancer cells. Our molecular mechanic studies revealed NADA degraded the levels of E6/E7 oncoproteins through ROS-mediated ubiquitin-dependent proteasome system activation. This is the first report that demonstrates antimycin alkaloids analogue induces the degradation of high-risk HPV E6/E7 oncoproteins and finally induces apoptosis in cervical cancer cells. The present work suggested that these analogues could serve as lead compounds for the development of HPV-infected cervical cancer therapeutic agents, as well as research tools for the study of E6/E7 functions.