Title
Marine Streptomyces sp. derived antimycin analogues suppress HeLa cells via depletion HPV E6/E7 mediated by ROS-dependent ubiquitin–proteasome system
Author
Weiyi Zhang, Qian Che, Hongsheng Tan, Xin Qi, Jing Li, Dehai Li, Qianqun Gu, Tianjiao Zhu, Ming Liu
Year
2017
Journal
Scientific Reports
Abstract
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.
Full Article
Instrument
J-715
Keywords
Circular dichroism, Absolute configuration, Natural products