title: Ophiobolin O isolated from Aspergillus ustus induces G1 arrest of MCF-7 cells through interaction with AKT/GSK3β/cyclin D1 signaling.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Basic Medical Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China. lvcuiting961021@126.com.
authors.forename: Cuiting
authors.initials: C
authors.lastname: Lv
authors.affiliation: Teaching Management Department, Yangpu Hospital, Tongji University School of Medicine, 450 Tengyue Road, Shanghai 200090, China. wendy_yes1@sina.com.
authors.forename: Wenxing
authors.initials: W
authors.lastname: Qin
authors.affiliation: 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.
authors.forename: Tonghan
authors.initials: T
authors.lastname: Zhu
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Basic Medical Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China. sjwei8012@hotmail.com.
authors.forename: Shanjian
authors.initials: S
authors.lastname: Wei
authors.affiliation: Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China. kuihong31@whu.edu.cn.
authors.forename: Kui
authors.initials: K
authors.lastname: Hong
authors.affiliation: 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.
authors.forename: Weiming
authors.initials: W
authors.lastname: Zhu
authors.affiliation: VIP Medicine Department, Changhai Hospital, Shanghai 200433, China. rhchen1964@sohu.com.
authors.forename: Ruohua
authors.initials: R
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Basic Medical Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China. huangcaig@hotmail.com.
authors.forename: Caiguo
authors.initials: C
authors.lastname: Huang
mesh_terms: D000818:Animals; D001230:Aspergillus / Q000737:chemistry*; D001943:Breast Neoplasms / Q000188:drug therapy; D019938:Cyclin D1 / Q000187:drug effects*; D005260:Female; D016193:G1 Phase / Q000187:drug effects*; D038362:Glycogen Synthase Kinase 3 / Q000187:drug effects*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D061986:MCF-7 Cells / Q000187:drug effects*; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D051058:Oncogene Protein v-akt / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D054830:Sesterterpenes / Q000302:isolation & purification / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D054830:Sesterterpenes; D019938:Cyclin D1; C101214:ophiobolin C; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051058:Oncogene Protein v-akt; D038362:Glycogen Synthase Kinase 3