Department of Medical Oncology, The 5th Affiliated Hospital of Guangzhou Medical University, Guangzhou, PR China.
Cancer Hospital and Cancer Research Institute, Guangzhou Medical University, Guangzhou, PR China.
Cancer Lett. 2017 Dec 28;411:1-11. doi: 10.1016/j.canlet.2017.09.027. Epub 2017 Sep 28.
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 previous in vitro studies 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.
越来越多的证据表明，治疗诱导的衰老（TIS）是一种新的治疗方法，即用低剂量的治疗药物或辐射来诱导衰老，从而抑制肿瘤的发展。我们之前的体外研究表明，低剂量的二甲双胍通过激活 AMP 激活的蛋白激酶（AMPK）和抑制 Sirtuin 1（SIRT1）去乙酰化酶活性，促进肝癌细胞衰老而不是凋亡。然而，AMPK 和 SIRT1 之间的复杂关系以及它们如何合作诱导衰老仍然难以捉摸。我们在这里表明，持续暴露于低浓度的二甲双胍会导致人肝癌（HCC）小鼠异种移植模型中 AMPK 的激活，从而导致衰老。有趣的是，AMPK 通过在肝癌细胞中二甲双胍介导的衰老过程中的直接磷酸化来反向调节 SIRT1。综上所述，这些发现表明，低剂量的二甲双胍可能可被用作 HCC 的 TIS 诱导治疗药物，通过 AMPK-SIRT1 途径诱导 HCC 细胞衰老来实现这一目的。
