Metformin and the ATM DNA damage response (DDR): accelerating the onset of stress-induced senescence to boost protection against cancer.
Metformin and the ATM DNA damage response (DDR): accelerating the onset of stress-induced senescence to boost protection against cancer.
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DOI：
10.18632/aging.100407
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发表时间：
2011-11
期刊：
影响因子：
--
通讯作者：
Vazquez-Martin A
中科院分区：
文献类型：
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作者：
Menendez JA;Cufí S;Oliveras-Ferraros C;Martin-Castillo B;Joven J;Vellon L;Vazquez-Martin A
通过激活共济失调毛细血管扩张突变（ATM）介导的DNA损伤反应（DDR），AMPK激动剂二甲双胍可能使细胞对进一步的损伤敏感，从而模拟癌前刺激，诱导针对致癌作用的内在屏障。在此，我们提出了一个新的假设，即二甲双胍可能在癌前细胞获得干细胞/肿瘤起始特性之前起组织清除剂的作用。由于糖酵解增强（瓦尔堡效应）通过保护肿瘤起始细胞免受线粒体呼吸诱导的氧化应激的促衰老效应，在肿瘤起始细胞获得干细胞样特性中发挥因果作用，因此二甲双胍破坏糖酵解代谢型的能力可能会产生一种在代谢上受到保护以防止永生化的细胞表型。二甲双胍造成的生物能量危机可能涉及线粒体生物合成和氧化应激增强，可通过预激活ATM依赖性假DDR降低细胞衰老的阈值。这允许响应于额外的致癌应激而加速细胞衰老的开始。通过推动癌细胞使用氧化磷酸化而不是糖酵解，二甲双胍可以挽救细胞表面主要组织相容性复合物I类（MHC-I）表达，该表达被致癌转化下调，这是肿瘤细胞避免细胞毒性T淋巴细胞（CTL）适应性免疫反应的关键适应。除了在细胞自主水平恢复肿瘤免疫监视外，二甲双胍还可激活衰老相关分泌表型（SASP）以加强衰老生长停滞，这可能以非细胞自主方式触发衰老细胞的免疫介导清除。通过减少逃离衰老抗肿瘤屏障的可能性，二甲双胍的净效应应是显著减少组织中功能障碍性癌前细胞的蓄积，包括具有引发肿瘤能力的细胞。由于已证明终生或晚期清除衰老细胞可预防或延迟年龄相关疾病的发作或进展，二甲双胍的组织清除功能可抑制癌前/衰老肿瘤细胞的恶性/转移进展，并延长人类寿命。
By activating the ataxia telangiectasia mutated (ATM)-mediated DNA Damage Response (DDR), the AMPK agonist metformin might sensitize cells against further damage, thus mimicking the precancerous stimulus that induces an intrinsic barrier against carcinogenesis. Herein, we present the new hypothesis that metformin might function as a tissue sweeper of pre-malignant cells before they gain stem cell/tumor initiating properties. Because enhanced glycolysis (the Warburg effect) plays a causal role in the gain of stem-like properties of tumor-initiating cells by protecting them from the pro-senescent effects of mitochondrial respiration-induced oxidative stress, metformin's ability to disrupt the glycolytic metabotype may generate a cellular phenotype that is metabolically protected against immortalization. The bioenergetic crisis imposed by metformin, which may involve enhanced mitochondrial biogenesis and oxidative stress, can lower the threshold for cellular senescence by pre-activating an ATM-dependent pseudo-DDR. This allows an accelerated onset of cellular senescence in response to additional oncogenic stresses. By pushing cancer cells to use oxidative phosphorylation instead of glycolysis, metformin can rescue cell surface major histocompatibility complex class I (MHC-I) expression that is downregulated by oncogenic transformation, a crucial adaptation of tumor cells to avoid the adaptive immune response by cytotoxic T-lymphocytes (CTLs). Aside from restoration of tumor immunosurveillance at the cell-autonomous level, metformin can activate a senescence-associated secretory phenotype (SASP) to reinforce senescence growth arrest, which might trigger an immune-mediated clearance of the senescent cells in a non-cell-autonomous manner. By diminishing the probability of escape from the senescence anti-tumor barrier, the net effect of metformin should be a significant decrease in the accumulation of dysfunctional, pre-malignant cells in tissues, including those with the ability to initiate tumors. As life-long or late-life removal of senescent cells has been shown to prevent or delay the onset or progression of age-related disorders, the tissue sweeper function of metformin may inhibit the malignant/metastatic progression of pre-malignant/senescent tumor cells and increase the human lifespan.