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首页> 外文期刊>Cell cycle >Metformin targets Stat3 to inhibit cell growth and induce apoptosis in triple-negative breast cancers
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Metformin targets Stat3 to inhibit cell growth and induce apoptosis in triple-negative breast cancers

机译：二甲双胍靶向Stat3以抑制三阴性乳腺癌中的细胞生长并诱导细胞凋亡

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A distinct group of breast cancers, called "basal" or "triple-negative" (TN) cancers, express both basal cytokeratins and the epidermal growth factor receptor but fail to express estrogen receptors, progesterone receptors or HER 2 and have stem-like or mesenchymal features. They are particularly aggressive, are frequently chemoresistant, with p53 mutation and upregulation of IL-6 and Stat3. Because TN cells are particularly sensitive to the anti-diabetic agent metformin, we hypothesized that it may target JAK2/Stat3 signaling. The effects of metformin upon Stat3 expression and activation were examined in four human TN cell lines. Metformin's effects were also studied in sublines with forced overexpression of constitutively active (CA) Stat3 as well as lines with stable knockdown of Stat3. Metformin inhibited Stat3 activation (P-Stat3) at Tyr705 and Ser727 and downstream signaling in each of the four parental cell lines. CA-Stat3 transfection attenuated, whereas Stat3 knockdown enhanced, the effects of metformin upon growth inhibition and apoptosis induction. A Stat3-specific inhibitor acted synergistically with metformin in reducing cell growth and inducing apoptosis. An mTOR inhibitor showed no significant interaction with metformin. In summary, Stat3 is a critical regulator of metformin action in TN cancer cells, providing the potential for enhancing metformin's efficacy in the clinical setting.
机译：称为“基础”或“三阴性”（TN）癌症的一组不同的乳腺癌，既表达基底细胞角蛋白也表达表皮生长因子受体，但不能表达雌激素受体，孕激素受体或HER 2，并且具有茎样或间质特征。它们特别具有攻击性，经常具有化学抗性，具有p53突变以及IL-6和Stat3的上调。因为TN细胞对抗糖尿病药二甲双胍特别敏感，所以我们假设它可能靶向JAK2 / Stat3信号传导。在四种人类TN细胞系中检查了二甲双胍对Stat3表达和激活的影响。在组成性活性（CA）Stat3强制过表达的亚系中以及在Stat3稳定敲低的系中也研究了二甲双胍的作用。二甲双胍抑制了四个亲本细胞系中每个细胞在Tyr705和Ser727处的Stat3激活（P-Stat3）和下游信号传导。 CA-Stat3转染减弱，而Stat3敲除增强，二甲双胍对生长抑制和凋亡诱导的影响。 Stat3特异性抑制剂与二甲双胍在减少细胞生长和诱导细胞凋亡中具有协同作用。 mTOR抑制剂与二甲双胍无明显相互作用。总之，Stat3是TN癌细胞中二甲双胍作用的关键调节剂，在临床环境中具有增强二甲双胍功效的潜力。

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