Département de Biochimie, Université de Montréal, Pavillon Roger-Gaudry 2900 boul. Édouard Montpetit, Montréal, QC, H3C 3J7, Canada.
Aging Cell. 2013 Jun;12(3):489-98. doi: 10.1111/acel.12075. Epub 2013 Apr 23.
We show that the antidiabetic drug metformin inhibits the expression of genes coding for multiple inflammatory cytokines seen during cellular senescence. Conditioned medium (CM) from senescent cells stimulates the growth of prostate cancer cells but treatment of senescent cells with metformin inhibited this effect. Bioinformatic analysis of genes downregulated by metformin suggests that the drug blocks the activity of the transcription factor NF-κB. In agreement, metformin prevented the translocation of NF-κB to the nucleus and inhibited the phosphorylation of IκB and IKKα/β, events required for activation of the NF-κB pathway. These effects were not dependent on AMPK activation or on the context of cellular senescence, as metformin inhibited the NF-κB pathway stimulated by lipopolysaccharide (LPS) in ampk null fibroblasts and in macrophages. Taken together, our results provide a novel mechanism for the antiaging and antineoplastic effects of metformin reported in animal models and in diabetic patients taking this drug.
我们表明，抗糖尿病药物二甲双胍可抑制细胞衰老过程中多种炎症细胞因子基因的表达。衰老细胞的条件培养基（CM）可刺激前列腺癌细胞的生长，但用二甲双胍处理衰老细胞可抑制这种作用。二甲双胍下调基因的生物信息学分析表明，该药物可阻断转录因子 NF-κB 的活性。一致地，二甲双胍可防止 NF-κB 向核内易位，并抑制 IκB 和 IKKα/β的磷酸化，这些事件是 NF-κB 途径激活所必需的。这些作用不依赖于 AMPK 激活或细胞衰老的背景，因为二甲双胍可抑制在ampk 缺失成纤维细胞和巨噬细胞中由脂多糖（LPS）刺激的 NF-κB 途径。总之，我们的结果为在动物模型和接受该药物治疗的糖尿病患者中观察到的二甲双胍的抗衰老和抗肿瘤作用提供了一种新的机制。
