Next Article in Journal
Paraoxonase-1 as a Regulator of Glucose and Lipid Homeostasis: Impact on the Onset and Progression of Metabolic Disorders
Next Article in Special Issue
Proposed Tandem Effect of Physical Activity and Sirtuin 1 and 3 Activation in Regulating Glucose Homeostasis
Previous Article in Journal
A Novel Method for Controlled Gene Expression via Combined Bleomycin and Plasmid DNA Electrotransfer
Previous Article in Special Issue
The Role of SIRT1 on DNA Damage Response and Epigenetic Alterations in Cancer
Open AccessArticle

Sorafenib-Induced Apoptosis in Hepatocellular Carcinoma Is Reversed by SIRT1

1
Center for Pediatric Research Leipzig (CPL), University Hospital for Children & Adolescents, Leipzig University, Liebigstr. 19, 04103 Leipzig, Germany
2
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; https://doi.org/10.3390/ijms20164048
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
Show Figures

Figure 1

MDPI and ACS Style

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.

Show more citation formats Show less citations formats
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop