Negative regulation of Sirtuin 1 by AMP-activated protein kinase promotes metformin-induced senescence in hepatocellular carcinoma xenografts.
Negative regulation of Sirtuin 1 by AMP-activated protein kinase promotes metformin-induced senescence in hepatocellular carcinoma xenografts.
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DOI：
10.1016/j.canlet.2017.09.027
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发表时间：
2017-12
期刊：
影响因子：
9.7
通讯作者：
Xinke Zhou;Jitao Chen;L. Chen;Xiao Feng;Zhaoyu Liu;La Hu;Zicheng Zeng;X. Jia;Min Liang
中科院分区：
文献类型：
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作者：
Xinke Zhou;Jitao Chen;L. Chen;Xiao Feng;Zhaoyu Liu;La Hu;Zicheng Zeng;X. Jia;Min Liang
越来越多的证据表明，治疗诱导衰老(TIS)是一种新的治疗方法，使用低剂量的治疗药物或辐射来诱导衰老，抑制肿瘤的发展。我们先前的体外研究表明，低剂量的二甲双胍通过激活AMP激活的蛋白激酶(AMPK)和失活Sirtuin 1(SIRT1)去乙酰基酶活性来促进肝癌细胞的衰老而不是凋亡。然而，AMPK和SIRT1之间的复杂关系，以及它们是如何协同诱导衰老的，仍然是未知的。我们在这里表明，持续暴露于低浓度的二甲双胍导致AMPK激活，在人肝细胞癌(HCC)的小鼠移植模型中，导致衰老。有趣的是，AMPK通过直接磷酸化在二甲双胍介导的肝癌细胞衰老过程中对SIRT1进行反调节。综上所述，这些发现表明，低剂量的二甲双胍可能被用于TIS诱导的肝癌治疗药物，这是通过AMPK-SIRT1途径诱导肝癌细胞衰老来实现的。
Increasing evidence suggests that therapy-induced senescence (TIS), a novel therapeutic approach in which low doses of therapeutic drugs or radiation are used to induce senescence, suppresses tumor development. Our previousin vitrostudies have demonstrated that a low dose of metformin promoted hepatoma cell senescence instead of apoptosis via activation of AMP-activated protein kinase (AMPK) and inactivation of Sirtuin 1 (SIRT1) deacetylase activity. However, the intricate relationship between AMPK and SIRT1, and how they cooperate to induce senescence remains elusive. We showed here that persistent exposure to a low concentration of metformin led to AMPK activation in a mouse xenograft model of human hepatocellular carcinoma (HCC), resulting in senescence. Intriguingly, AMPK counter-regulated SIRT1 via direct phosphorylation in metformin-mediated senescence in hepatoma cells. Taken together, these findings suggest that a low dose of metformin could potentially be used as a TIS-inducing therapeutic drug for HCC, and that this occurs by inducing senescence of HCC cells via the AMPK-SIRT1 pathway.