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

机译：二甲双胍通过靶向KLF5降解来抑制三阴性乳腺癌干细胞

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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.
机译：在乳腺癌亚型中，三阴性乳腺癌（TNBC）的预后最差，而没有有效的靶向疗法。二甲双胍是治疗2型糖尿病的一线药物，已被证明可选择性靶向乳腺癌干细胞。但是，二甲双胍在TNBC中的功效和作用机制尚不清楚。在这项研究中，我们证明了二甲双胍通过下调干细胞转录因子Krüppel样因子5（KLF5）及其下游靶基因（如Nanog和FGF-BP1）的表达来部分降低TNBC干细胞的百分比，在TNBC细胞系中。通过抑制TNBC细胞中的蛋白激酶A（PKA）活性，二甲双胍诱导的糖原合酶激酶3β（GSK3β）介导的KLF5蛋白磷酸化和降解。一致地，PKA激活剂增加了KLF5的表达水平。我们观察到人TNBC样品中p-CREB，p-GSK3β，KLF5和FGF-BP1蛋白水平呈正相关。这些发现表明二甲双胍可部分通过PKA-GSK3β-KLF5信号通路抑制TNBC干细胞。

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