title: Dual inhibiting OCT4 and AKT potently suppresses the propagation of human cancer cells.
abstract: AKT serves as an epigenetic modulator that links epigenetic regulation to cell survival and proliferation while the epigenetic mediator OCT4 critically controls stem cell pluripotency and self-renewal. Emerging evidence indicated their complicated interplays in cancer cells and cancer stem cells (CSCs), and inhibiting either one may activate the other. Thus, in this study, we propose a strategy to targeting both factors simultaneously. Firstly, a combination of an OCT4-specific shRNA and the specific AKT inhibitor Akti-1/2 potently suppressed the propagation of human embryonal carcinoma cells, adherent cancer cells and stem-like cancer cells, establishing the proof-of-concept that dual inhibiting OCT4 and AKT can effectively target various cancer cells. Next, we combined Akti-1/2 with metformin, a widely-prescribed drug for treating type 2 diabetes, which was reported to down-regulate OCT4 expression. The metformin + Akti-1/2 combo significantly altered multiple signaling and epigenetic pathways, induced growth arrest and cell death of adherent and stem-like glioblastoma U87 cells, and attenuated their tumorigenicity in vivo. Taken together, we demonstrate here that simultaneously targeting an epigenetic mediator and an epigenetic modulator, by dual inhibiting OCT4 and AKT, can have significantly improved efficacies over single treatment in suppressing the propagation of CSCs as well as the entire bulk of differentiated cancer cells.
authors.affiliation: State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China.
authors.forename: Wenxin
authors.initials: W
authors.lastname: Li
authors.affiliation: State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China.
authors.forename: Yanwen
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China.
authors.forename: Xiaoqian
authors.initials: X
authors.lastname: Zhang
authors.affiliation: State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Yang
authors.affiliation: State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China.
authors.forename: Songsong
authors.initials: S
authors.lastname: Dan
authors.affiliation: College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Tong
authors.initials: T
authors.lastname: Su
authors.affiliation: State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China.
authors.forename: Shiqi
authors.initials: S
authors.lastname: She
authors.affiliation: College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Weilai
authors.initials: W
authors.lastname: Dong
authors.affiliation: State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China.|Department of Pharmacy, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China.
authors.forename: Qingwei
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: Shanghai Center for Bioinformation Technology, Shanghai 201203, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Jia
authors.affiliation: State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China.
authors.forename: Hangping
authors.initials: H
authors.lastname: Yao
authors.affiliation: State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China.
authors.forename: Min
authors.initials: M
authors.lastname: Zheng
authors.affiliation: State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Kang
authors.affiliation: State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China.
authors.forename: Ying-Jie
authors.initials: YJ
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D063646:Carcinogenesis / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D044127:Epigenesis, Genetic / Q000187:drug effects; D005260:Female; D006801:Humans; D008687:Metformin / Q000494:pharmacology; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000235:genetics / Q000473:pathology*; D050814:Octamer Transcription Factor-3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D018874:Spheroids, Cellular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
chemical_list: D050814:Octamer Transcription Factor-3; D034741:RNA, Small Interfering; D008687:Metformin; D051057:Proto-Oncogene Proteins c-akt