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Open AccessArticle

Sorafenib-Induced Apoptosis in Hepatocellular Carcinoma Is Reversed by SIRT1

Center for Pediatric Research Leipzig (CPL), University Hospital for Children & Adolescents, Leipzig University, Liebigstr. 19, 04103 Leipzig, Germany
Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2019, 20(16), 4048;
Received: 11 July 2019 / Revised: 30 July 2019 / Accepted: 9 August 2019 / Published: 19 August 2019
(This article belongs to the Special Issue Sirtuins and Epigenetics in Aging and Diseases)
Sorafenib is a multi-kinase inhibitor and one of the few systemic treatment options for patients with advanced hepatocellular carcinomas (HCCs). Resistance to sorafenib develops frequently and could be mediated by the nicotinamide adenine dinucleotide (NAD)-dependent deacetylase sirtuin (SIRT)1. We aimed to test whether sorafenib efficacy is influenced by cellular NAD levels and NAD-dependent SIRT1 function. We analyzed sorafenib effects on apoptosis induction, NAD salvage, mitochondrial function, and related signaling pathways in HCC cell lines (HepG2, Hep3B, und HUH7) overexpressing SIRT1 or supplemented with the NAD metabolite nicotinamide mononucleotide (NMN) compared to controls. Treatment of HCC cell lines with sorafenib dose-dependently induced apoptosis and a significant decrease in cellular NAD concentrations. The SIRT1 protein was downregulated in HUH7 cells but not in Hep3B cells. After sorafenib treatment, mitochondrial respiration in permeabilized cells was lower, citrate synthase activity was attenuated, and cellular adenosine triphosphate (ATP) levels were decreased. Concomitant to increased phosphorylation of adenosine monophosphate (AMP)-activated protein kinase (AMPK), sorafenib treatment led to decreased activity of the mechanistic target of rapamycin (mTOR), indicative of energy deprivation. Transient overexpression of SIRT1, as well as NAD repletion by NMN, decreased sorafenib-induced apoptosis. We can, therefore, conclude that sorafenib influences the NAD/SIRT1/AMPK axis. Overexpression of SIRT1 could be an underlying mechanism of resistance to sorafenib treatment in HCC. View Full-Text
Keywords: mitochondria; AMP-activated protein kinase; mTOR; NAMPT; sorafenib; SIRT1 mitochondria; AMP-activated protein kinase; mTOR; NAMPT; sorafenib; SIRT1
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Garten, A.; Grohmann, T.; Kluckova, K.; Lavery, G.G.; Kiess, W.; Penke, M. Sorafenib-Induced Apoptosis in Hepatocellular Carcinoma Is Reversed by SIRT1. Int. J. Mol. Sci. 2019, 20, 4048.

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