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Sorafenib-Induced Apoptosis in Hepatocellular Carcinoma Is Reversed by SIRT1

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...

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Autores principales: Garten, Antje, Grohmann, Theresa, Kluckova, Katarina, Lavery, Gareth G., Kiess, Wieland, Penke, Melanie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6719220/
https://www.ncbi.nlm.nih.gov/pubmed/31430957
http://dx.doi.org/10.3390/ijms20164048
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author Garten, Antje
Grohmann, Theresa
Kluckova, Katarina
Lavery, Gareth G.
Kiess, Wieland
Penke, Melanie
author_facet Garten, Antje
Grohmann, Theresa
Kluckova, Katarina
Lavery, Gareth G.
Kiess, Wieland
Penke, Melanie
author_sort Garten, Antje
collection PubMed
description 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.
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spelling pubmed-67192202019-09-10 Sorafenib-Induced Apoptosis in Hepatocellular Carcinoma Is Reversed by SIRT1 Garten, Antje Grohmann, Theresa Kluckova, Katarina Lavery, Gareth G. Kiess, Wieland Penke, Melanie Int J Mol Sci Article 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. MDPI 2019-08-19 /pmc/articles/PMC6719220/ /pubmed/31430957 http://dx.doi.org/10.3390/ijms20164048 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Garten, Antje
Grohmann, Theresa
Kluckova, Katarina
Lavery, Gareth G.
Kiess, Wieland
Penke, Melanie
Sorafenib-Induced Apoptosis in Hepatocellular Carcinoma Is Reversed by SIRT1
title Sorafenib-Induced Apoptosis in Hepatocellular Carcinoma Is Reversed by SIRT1
title_full Sorafenib-Induced Apoptosis in Hepatocellular Carcinoma Is Reversed by SIRT1
title_fullStr Sorafenib-Induced Apoptosis in Hepatocellular Carcinoma Is Reversed by SIRT1
title_full_unstemmed Sorafenib-Induced Apoptosis in Hepatocellular Carcinoma Is Reversed by SIRT1
title_short Sorafenib-Induced Apoptosis in Hepatocellular Carcinoma Is Reversed by SIRT1
title_sort sorafenib-induced apoptosis in hepatocellular carcinoma is reversed by sirt1
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6719220/
https://www.ncbi.nlm.nih.gov/pubmed/31430957
http://dx.doi.org/10.3390/ijms20164048
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