机构：[1]Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China[2]Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, China[3]Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, China[4]State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, China[5]School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, China[6]Department of Pathology, First Affiliated Hospital of Kunming Medical University, Kunming, China医技科室病理科昆明医科大学附属第一医院[7]Cancer Hospital, Kunming Medical University, Kunming, China昆明医科大学附属第一医院
Out of the breast cancer subtypes, triple-negative breast cancer (TNBC) has the poorest prognosis without effective targeted therapies. Metformin, a first-line drug for type 2 diabetes mellitus, was demonstrated to target breast cancer stem cells selectively. However, the efficiency and the mechanism of action of metformin in TNBC are unclear. In this study, we demonstrated that metformin decreased the percentage of TNBC stem cells partially through the downregulation of the expression of the stem cell transcription factor Kruppel-like factor 5 (KLF5) and its downstream target genes, such as Nanog and FGF-BP1, in TNBC cell lines. Metformin induced glycogen synthase kinase-3 beta (GSK3 beta)-mediated KLF5 protein phosphorylation and degradation through the inhibition of protein kinase A (PKA) activity in TNBC cells. Consistently, PKA activators increased the expression levels of KLF5. We observed a positive correlation between p-CREB, p-GSK3 beta, KLF5 and FGF-BP1 protein levels in human TNBC samples. These findings suggest that metformin suppresses TNBC stem cells partially through the PKA-GSK3 beta-KLF5 signaling pathway.
基金：
National Nature Science Foundation of
China (81325016 and U1602221 to CC, 81672639 to ZZ,
U1502222, 81322038 and 81272930 to RL), the Yunnan
Applied Basic Research Key Projects (2015FA027 to RL), the
West Light Foundation of the Chinese Academy of Sciences
(to RL) and the Youth Innovation Promotion Association and
the Chinese Academy of Sciences (to RL).
第一作者机构：[1]Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China[2]Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, China
通讯作者：
推荐引用方式(GB/T 7714)：
Shi Peiguo,Liu Wenjing,Tala,et al.Metformin suppresses triple-negative breast cancer stem cells by targeting KLF5 for degradation[J].CELL DISCOVERY.2017,3:doi:10.1038/celldisc.2017.10.
APA：
Shi, Peiguo,Liu, Wenjing,Tala,Wang, Haixia,Li, Fubing...&Chen, Ceshi.(2017).Metformin suppresses triple-negative breast cancer stem cells by targeting KLF5 for degradation.CELL DISCOVERY,3,
MLA：
Shi, Peiguo,et al."Metformin suppresses triple-negative breast cancer stem cells by targeting KLF5 for degradation".CELL DISCOVERY 3.(2017)
