Marine Streptomyces sp. derived antimycin analogues suppress HeLa cells via depletion HPV E6/E7 mediated by ROS-dependent ubiquitin-proteasome system.
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.
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.
Weiyi
W
Zhang
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.|Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, 266237, People's Republic of China.
Qian
Q
Che
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.
Hongsheng
H
Tan
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.|Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, 266237, People's Republic of China.
Xin
X
Qi
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.|Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, 266237, People's Republic of China.
Jing
J
Li
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.|Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, 266237, People's Republic of China.
Dehai
D
Li
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.|Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, 266237, People's Republic of China.
Qianqun
Q
Gu
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.|Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, 266237, People's Republic of China.
Tianjiao
T
Zhu
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.|Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, 266237, People's Republic of China.
Ming
M
Liu
D000968:Antimycin A / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000302:isolation & purification / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000302:isolation & purification / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D002461:Cell Line, Transformed; D049109:Cell Proliferation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D015870:Gene Expression; D006367:HeLa Cells; D052161:Human papillomavirus 18 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity; D006801:Humans; D009856:Oncogene Proteins, Viral / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000378:metabolism; D059748:Proteolysis; D017382:Reactive Oxygen Species / Q000819:agonists / Q000378:metabolism; D013302:Streptomyces / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship; D025801:Ubiquitin / Q000378:metabolism
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; C052603:E6 protein, Human papillomavirus type 18; C052633:E7 protein, Human papillomavirus type 18; D009856:Oncogene Proteins, Viral; D017382:Reactive Oxygen Species; D025801:Ubiquitin; C032456:antimycin; D000968:Antimycin A; D046988:Proteasome Endopeptidase Complex