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... 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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Cancer Letters Elsevier

Negative regulation of Sirtuin 1 by AMP-activated protein kinase promotes metformin-induced senescence in hepatocellular carcinoma xenografts

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Publisher
Elsevier
Copyright
Copyright © 2017 Elsevier Ltd
ISSN
0304-3835
D.O.I.
10.1016/j.canlet.2017.09.027
Publisher site
See Article on Publisher Site

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.

Journal

Cancer LettersElsevier

Published: Dec 28, 2017

References

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