Marine Streptomyces sp. derived antimycin analogues suppress HeLa cells via depletion HPV E6/E7 mediated by ROS-dependent ubiquitin-proteasome system

Weiyi Zhang; Qian Che; Hongsheng Tan; Xin Qi; Jing Li; Dehai Li; Qianqun Gu; Tianjiao Zhu; Ming Liu

doi:10.1038/srep42180

Marine Streptomyces sp. derived antimycin analogues suppress HeLa cells via depletion HPV E6/E7 mediated by ROS-dependent ubiquitin-proteasome system

Sci Rep. 2017 Feb 8:7:42180. doi: 10.1038/srep42180.

Authors

Weiyi Zhang¹, Qian Che^{1

2}, Hongsheng Tan¹, Xin Qi^{1

2}, Jing Li^{1

2}, Dehai Li^{1

2}, Qianqun Gu^{1

2}, Tianjiao Zhu^{1

2}, Ming Liu^{1

2}

Affiliations

¹ Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, People's Republic of China.
² Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, 266237, People's Republic of China.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antimycin A / analogs & derivatives*
Antimycin A / chemical synthesis
Antimycin A / isolation & purification
Antimycin A / pharmacology
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / isolation & purification
Antineoplastic Agents / pharmacology*
Cell Cycle / drug effects
Cell Cycle / genetics
Cell Line, Transformed
Cell Proliferation / drug effects
DNA-Binding Proteins / antagonists & inhibitors*
DNA-Binding Proteins / biosynthesis
DNA-Binding Proteins / genetics
Female
Gene Expression
HeLa Cells
Human papillomavirus 18 / drug effects*
Human papillomavirus 18 / genetics
Human papillomavirus 18 / metabolism
Human papillomavirus 18 / pathogenicity
Humans
Oncogene Proteins, Viral / antagonists & inhibitors*
Oncogene Proteins, Viral / biosynthesis
Oncogene Proteins, Viral / genetics
Proteasome Endopeptidase Complex / drug effects
Proteasome Endopeptidase Complex / metabolism
Proteolysis
Reactive Oxygen Species / agonists
Reactive Oxygen Species / metabolism
Streptomyces / chemistry*
Streptomyces / metabolism
Structure-Activity Relationship
Ubiquitin / metabolism

Substances

Antineoplastic Agents
DNA-Binding Proteins
E6 protein, Human papillomavirus type 18
E7 protein, Human papillomavirus type 18
Oncogene Proteins, Viral
Reactive Oxygen Species
Ubiquitin
antimycin
Antimycin A
Proteasome Endopeptidase Complex