Metformin lowers the threshold for stress-induced senescence A role for the microRNA-200 family and miR-205
Metformin lowers the threshold for stress-induced senescence A role for the microRNA-200 family and miR-205
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DOI：
10.4161/cc.11.6.19665
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发表时间：
2012-03-15
期刊：
影响因子：
4.3
通讯作者：
Menendez, Javier A.
中科院分区：
文献类型：
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作者：
Cufi, Silvia;Vazquez-Martin, Alejandro;Menendez, Javier A.
我们已经验证了这样的假设，即抗糖尿病双胍二甲双胍可用于操纵应激诱导衰老（SIS）的阈值，从而加速致癌刺激引起的癌症保护性细胞衰老的发生。使用衰老倾向的小鼠胚胎成纤维细胞（MEF），我们评估了二甲双胍治疗是否改变了响应DNA损伤诱导剂而激活的衰老表型。二甲双胍显著增加了响应多柔比星进入衰老阶段的MEF的数量，多柔比星是一种通过激活DNA损伤信号通路诱导细胞衰老的蒽环类药物（例如，例如，在一个实施例中，ATM/ATR）以活性氧（ROS）依赖的方式。使用WI-38和BJ-1人二倍体成纤维细胞（HDF），我们探讨了在其整个复制寿命期间补充二甲双胍是否可以促进复制衰老生物标志物的早期出现。慢性二甲双胍通过加速复制潜能的丧失和复制衰老相关生物标志物的获得显著缩短了HDFs的寿命（e.例如，在一个实施例中，增大和扁平的细胞形状、阵列排列的丧失、细胞内和细胞外碎片的积累以及SA-β-gal阳性染色）。二甲双胍作为一种真正的应激剂发挥作用，在BJ-1 HDF中诱导单调的、剂量依赖性的、SIS样反应，其对ROS诱导的早衰具有高度抗性。二甲双胍诱导的BJ-1成纤维细胞中的SIS伴随着属于miR-200家族的几种microRNA（miR-200 a、miR-141和miR 429）和miR-205的显著活化，从而模拟了最近描述的ROS通过特异性上调抗EMT（上皮-间充质转化）miR-200使癌细胞化学增敏的能力。由于干细胞的无限增殖潜力是由它们对SIS的代谢不敏感性引起的，我们最终测试了二甲双胍治疗是否可以规避应激（例如，例如，在一个实施例中，诱导多能干细胞（iPSC）的ROS抗性表型。二甲双胍处理显著减少了iPSC集落的数量和大小，并显著减少了多能性标志物碱性磷酸酶的染色。总之，我们目前的研究结果首次揭示了二甲双胍可以有效降低SIS产生“应激”细胞表型的阈值，所述细胞表型对致癌样刺激物（包括DNA损伤、增殖和/或干性诱导物）预致敏。
We have tested the hypothesis that the antidiabetic biguanide metformin can be used to manipulate the threshold for stress-induced senescence (SIS), thus accelerating the onset of cancer-protective cellular senescence in response to oncogenic stimuli. Using senescence-prone murine embryonic fibroblasts (MEFs), we assessed whether metformin treatment modified the senescence phenotype that is activated in response to DNA damaging inducers. Metformin significantly enhanced the number of MEFs entering a senescent stage in response to doxorubicin, an anthracycline that induces cell senescence by activating DNA damage signaling pathways (e. g., ATM/ATR) in a reactive oxygen species (ROS)-dependent manner. Using WI-38 and BJ-1 human diploid fibroblasts (HDFs), we explored whether metformin supplementation throughout their entire replicative lifespan may promote the early appearance of the biomarkers of replicative senescence. Chronic metformin significantly reduced HDFs' lifespan by accelerating both the loss of replicative potential and the acquisition of replicative senescence-related biomarkers (e. g., enlarged and flattened cell shapes, loss of arrayed arrangement, accumulation of intracellular and extracellular debris and SA-beta-gal-positive staining). Metformin functioned as a bona fide stressful agent, inducing monotonic, dose-dependent, SIS-like responses in BJ-1 HDFs, which are highly resistant to ROS-induced premature senescence. Metformin-induced SIS in BJ-1 fibroblasts was accompanied by the striking activation of several microRNAs belonging to the miR-200s family (miR-200a, miR-141 and miR429) and miR-205, thus mimicking a recently described ability of ROS to chemosensitize cancer cells by specifically upregulating anti-EMT (epithelial-to-mesenchymal transition) miR-200s. Because the unlimited proliferative potential of stem cells results from their metabolic refractoriness to SIS, we finally tested if metformin treatment could circumvent the stress (e. g., ROS)-resistant phenotype of induced pluripotent stem cells (iPSCs). Metformin treatment drastically reduced both the number and the size of iPSC colonies and notably diminished the staining of the pluripotency marker alkaline phosphatase. Our current findings, altogether, reveal for the first time that metformin can efficiently lower the threshold for SIS to generate an "stressed" cell phenotype that becomes pre-sensitized to oncogenic-like stimuli, including DNA damaging, proliferative and/or stemness inducers.