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Mar Drugs. 2015 Jan 16;13(1):431-43. doi: 10.3390/md13010431.

Ophiobolin O isolated from Aspergillus ustus induces G1 arrest of MCF-7 cells through interaction with AKT/GSK3β/cyclin D1 signaling.

Author information

1
Department of Biochemistry and Molecular Biology, College of Basic Medical Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China. lvcuiting961021@126.com.
2
Teaching Management Department, Yangpu Hospital, Tongji University School of Medicine, 450 Tengyue Road, Shanghai 200090, China. wendy_yes1@sina.com.
3
Key Laboratory of Marine Drugs, Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China. sdueduzth@126.com.
4
Department of Biochemistry and Molecular Biology, College of Basic Medical Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China. sjwei8012@hotmail.com.
5
Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China. kuihong31@whu.edu.cn.
6
Key Laboratory of Marine Drugs, Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China. weimingzhu@ouc.edu.cn.
7
VIP Medicine Department, Changhai Hospital, Shanghai 200433, China. rhchen1964@sohu.com.
8
Department of Biochemistry and Molecular Biology, College of Basic Medical Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China. huangcaig@hotmail.com.

Abstract

Ophiobolin O is a member of ophiobolin family, which has been proved to be a potent anti-tumor drug candidate for human breast cancer. However, the anti-tumor effect and the mechanism of ophiobolin O remain unclear. In this study, we further verified ophiobolin O-induced G1 phase arrest in human breast cancer MCF-7 cells, and found that ophiobolin O reduced the phosphorylation level of AKT and GSK3β, and induced down-regulation of cyclin D1. The inverse docking (INVDOCK) analysis indicated that ophiobolin O could bind to GSK3β, and GSK3β knockdown abolished cyclin D1 degradation and G1 phase arrest. Pre-treatment with phosphatase inhibitor sodium or thovanadate halted dephosphorylation of AKT and GSK3β, and blocked ophiobolin O-induced G1 phase arrest. These data suggest that ophiobolin O may induce G1 arrest in MCF-7 cells through interaction with AKT/GSK3β/cyclin D1 signaling. In vivo, ophiobolin O suppressed tumor growth and showed little toxicity in mouse xenograft models. Overall, these findings provide theoretical basis for the therapeutic use of ophiobolin O.

PMID:
25603341
PMCID:
PMC4306945
DOI:
10.3390/md13010431
[Indexed for MEDLINE]
Free PMC Article

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