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首页> 外文期刊>Cell cycle >Metformin lowers the threshold for stress-induced senescence: A role for the microRNA-200 family and miR-205
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Metformin lowers the threshold for stress-induced senescence: A role for the microRNA-200 family and miR-205

机译：二甲双胍降低了应激诱导的衰老阈值：microRNA-200家族和miR-205的作用

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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-β-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.
机译：我们已经测试了抗糖尿病双胍二甲双胍可用于操纵应激诱导衰老（SIS）的阈值的假设，从而加速了对致癌性刺激的癌症保护性细胞衰老的发作。使用易于衰老的鼠类胚胎成纤维细胞（MEF），我们评估了二甲双胍治疗是否改变了衰老表型，该表型响应DNA损伤诱导物而被激活。二甲双胍显着增加了对阿霉素的反应，进入衰老阶段的MEF的数量。阿霉素是一种以依赖活性氧（ROS）的方式激活DNA损伤信号传导途径（例如ATM / ATR）来诱导细胞衰老的蒽环类药物。使用WI-38和BJ-1人类二倍体成纤维细胞（HDF），我们探索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的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性衰老相关生物标记物的获得（例如，细胞形状的扩大和扁平化，排列排列的丧失，细胞内和细胞外碎片的积累以及SA-β-gal）的出现，大大缩短了HDF的寿命。 -阳性染色）。二甲双胍起着真正的压力作用，在BJ-1 HDF中诱导单调，剂量依赖性，SIS样反应，这些反应对ROS诱导的早衰具有高度抵抗力。 BJ-1成纤维细胞中二甲双胍诱导的SIS伴随着miR-200s家族的几个microRNA（miR-200a，miR-141和miR429）和miR-205的显着激活，从而模仿了最近描述的ROS通过特异性上调抗EMT（上皮到间质转化）miR-200s来化学增敏癌细胞。由于干细胞的无限增殖潜力是由它们对SIS的新陈代谢难治性导致的，因此我们最终测试了二甲双胍治疗是否可以绕过诱导性多能干细胞（iPSC）的抗应激（例如ROS）表型。二甲双胍治疗显着减少了iPSC菌落的数量和大小，并显着减少了多能性标记碱性磷酸酶的染色。我们目前的发现总共首次揭示了二甲双胍可以有效降低SIS的阈值，以产生“应激”细胞表型，使其对致癌样刺激物（包括DNA损伤，增殖和/或茎诱导剂）预先敏感。

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