Metformin targets Stat3 to inhibit cell growth and induce apoptosis in triple-negative breast cancers
Metformin targets Stat3 to inhibit cell growth and induce apoptosis in triple-negative breast cancers
复制标题
DOI：
10.4161/cc.11.2.18813
复制
发表时间：
2012-01-15
期刊：
影响因子：
4.3
通讯作者：
Thor, Ann D.
中科院分区：
文献类型：
--
作者：
Deng, Xin-Sheng;Wang, Shuiliang;Thor, Ann D.
有一类独特的乳腺癌，被称为“基底”或“三阴性”（TN）癌，既表达基底细胞角蛋白，也表达表皮生长因子受体，但不表达雌激素受体、孕激素受体或HER 2，并具有茎样或间充质特征。它们具有特别的侵袭性，通常具有化疗耐药性，伴有p53突变和IL-6和Stat3的上调。由于TN细胞对抗糖尿病药物二甲双胍特别敏感，我们假设它可能靶向JAK2/Stat3信号通路。研究了二甲双胍对人TN细胞系Stat3表达和激活的影响。二甲双胍的作用也被研究在强制过表达构成活性（CA） Stat3的亚系和稳定敲低Stat3的亚系中。二甲双胍抑制了四种亲本细胞系中Tyr705和Ser727位点的Stat3激活（P-Stat3）以及下游信号。CA-Stat3转染减弱，而Stat3敲低增强二甲双胍对生长抑制和细胞凋亡诱导的作用。stat3特异性抑制剂与二甲双胍协同作用，降低细胞生长和诱导细胞凋亡。mTOR抑制剂与二甲双胍无明显相互作用。总之，Stat3是二甲双胍在TN癌细胞中作用的关键调节因子，为增强二甲双胍在临床环境中的疗效提供了潜力。
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.