Metformin suppresses triple-negative breast cancer stem cells by targeting KLF5 for degradation

Peiguo Shi; Wenjing Liu; Tala; Haixia Wang; Fubing Li; Hailin Zhang; Yingying Wu; Yanjie Kong; Zhongmei Zhou; Chunyan Wang; Wenlin Chen; Rong Liu; Ceshi Chen

doi:10.1038/celldisc.2017.10

Metformin suppresses triple-negative breast cancer stem cells by targeting KLF5 for degradation

Cell Discov. 2017 Apr 18:3:17010. doi: 10.1038/celldisc.2017.10. eCollection 2017.

Authors

Peiguo Shi^{1

2}, Wenjing Liu^{1

3}, Tala⁴, Haixia Wang^{1

5}, Fubing Li^{1

2}, Hailin Zhang¹, Yingying Wu^{1

2

6}, Yanjie Kong¹, Zhongmei Zhou¹, Chunyan Wang⁶, Wenlin Chen⁷, Rong Liu¹, Ceshi Chen¹

Affiliations

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.
⁷ Cancer Hospital, Kunming Medical University, Kunming, China.

Abstract

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 Krüppel-like factor 5 (KLF5) and its downstream target genes, such as Nanog and FGF-BP1, in TNBC cell lines. Metformin induced glycogen synthase kinase-3β (GSK3β)-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-GSK3β, KLF5 and FGF-BP1 protein levels in human TNBC samples. These findings suggest that metformin suppresses TNBC stem cells partially through the PKA-GSK3β-KLF5 signaling pathway.

Keywords: KLF5; PKA; metformin; stem cells; triple-negative breast cancer.