Negative regulation of Sirtuin 1 by AMP-activated protein kinase promotes metformin-induced senescence in hepatocellular carcinoma xenografts. (28th December 2017)

• Record Type: Journal Article
• Authors: Zhou, Xinke; Chen, Jitao; Chen, Liangcai; Feng, Xiao; Liu, Zhaoyu; Hu, La; Zeng, Zicheng; Jia, Xiaoting; Liang, Min; Shi, Boyun; Yi, Gao; Liu, Jifang
• Is Part Of: Cancer letters. Volume 411(2018)
• Page Start: 1
• Page End: 11
• Publication Date: 2017-12-28
• Subjects: Metformin -- Sirtuin 1 -- AMP-activated protein kinase -- Cellular senescence -- Hepatocellular carcinoma; SIRT1 Sirtuin 1 -- AMPK AMP-activated Protein Kinase -- TIS therapy-induced senescence -- SA-β-gal senescence-associated β-galactosidase; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2017.09.027
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: 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. Highlights: A low dose of metformin has an anticancer effect in HCC xenografts by inducing senescence. AMPK counter-regulated SIRT1 via direct phosphorylation in metformin-mediated senescence in hepatoma cells. Targeting the AMPK/SIRT1 pathway is a promising therapeutic strategy for HCC patients.