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Sofosbuvir Activates EGFR-Dependent Pathways in Hepatoma Cells with Implications for Liver-Related Pathological Processes

Direct acting antivirals (DAAs) revolutionized the therapy of chronic hepatitis C infection. However, unexpected high recurrence rates of hepatocellular carcinoma (HCC) after DAA treatment became an issue in patients with advanced cirrhosis and fibrosis. In this study, we aimed to investigate an imp...

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Autores principales: Bojkova, Denisa, Westhaus, Sandra, Costa, Rui, Timmer, Lejla, Funkenberg, Nora, Korencak, Marek, Streeck, Hendrik, Vondran, Florian, Broering, Ruth, Heinrichs, Stefan, Lang, Karl S, Ciesek, Sandra
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7225999/
https://www.ncbi.nlm.nih.gov/pubmed/32316635
http://dx.doi.org/10.3390/cells9041003
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author Bojkova, Denisa
Westhaus, Sandra
Costa, Rui
Timmer, Lejla
Funkenberg, Nora
Korencak, Marek
Streeck, Hendrik
Vondran, Florian
Broering, Ruth
Heinrichs, Stefan
Lang, Karl S
Ciesek, Sandra
author_facet Bojkova, Denisa
Westhaus, Sandra
Costa, Rui
Timmer, Lejla
Funkenberg, Nora
Korencak, Marek
Streeck, Hendrik
Vondran, Florian
Broering, Ruth
Heinrichs, Stefan
Lang, Karl S
Ciesek, Sandra
author_sort Bojkova, Denisa
collection PubMed
description Direct acting antivirals (DAAs) revolutionized the therapy of chronic hepatitis C infection. However, unexpected high recurrence rates of hepatocellular carcinoma (HCC) after DAA treatment became an issue in patients with advanced cirrhosis and fibrosis. In this study, we aimed to investigate an impact of DAA treatment on the molecular changes related to HCC development and progression in hepatoma cell lines and primary human hepatocytes. We found that treatment with sofosbuvir (SOF), a backbone of DAA therapy, caused an increase in EGFR expression and phosphorylation. As a result, enhanced translocation of EGFR into the nucleus and transactivation of factors associated with cell cycle progression, B-MYB and Cyclin D1, was detected. Serine/threonine kinase profiling identified additional pathways, especially the MAPK pathway, also activated during SOF treatment. Importantly, the blocking of EGFR kinase activity by erlotinib during SOF treatment prevented all downstream events. Altogether, our findings suggest that SOF may have an impact on pathological processes in the liver via the induction of EGFR signaling. Notably, zidovudine, another nucleoside analogue, exerted a similar cell phenotype, suggesting that the observed effects may be induced by additional members of this drug class.
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spelling pubmed-72259992020-05-18 Sofosbuvir Activates EGFR-Dependent Pathways in Hepatoma Cells with Implications for Liver-Related Pathological Processes Bojkova, Denisa Westhaus, Sandra Costa, Rui Timmer, Lejla Funkenberg, Nora Korencak, Marek Streeck, Hendrik Vondran, Florian Broering, Ruth Heinrichs, Stefan Lang, Karl S Ciesek, Sandra Cells Article Direct acting antivirals (DAAs) revolutionized the therapy of chronic hepatitis C infection. However, unexpected high recurrence rates of hepatocellular carcinoma (HCC) after DAA treatment became an issue in patients with advanced cirrhosis and fibrosis. In this study, we aimed to investigate an impact of DAA treatment on the molecular changes related to HCC development and progression in hepatoma cell lines and primary human hepatocytes. We found that treatment with sofosbuvir (SOF), a backbone of DAA therapy, caused an increase in EGFR expression and phosphorylation. As a result, enhanced translocation of EGFR into the nucleus and transactivation of factors associated with cell cycle progression, B-MYB and Cyclin D1, was detected. Serine/threonine kinase profiling identified additional pathways, especially the MAPK pathway, also activated during SOF treatment. Importantly, the blocking of EGFR kinase activity by erlotinib during SOF treatment prevented all downstream events. Altogether, our findings suggest that SOF may have an impact on pathological processes in the liver via the induction of EGFR signaling. Notably, zidovudine, another nucleoside analogue, exerted a similar cell phenotype, suggesting that the observed effects may be induced by additional members of this drug class. MDPI 2020-04-17 /pmc/articles/PMC7225999/ /pubmed/32316635 http://dx.doi.org/10.3390/cells9041003 Text en © 2020 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
Bojkova, Denisa
Westhaus, Sandra
Costa, Rui
Timmer, Lejla
Funkenberg, Nora
Korencak, Marek
Streeck, Hendrik
Vondran, Florian
Broering, Ruth
Heinrichs, Stefan
Lang, Karl S
Ciesek, Sandra
Sofosbuvir Activates EGFR-Dependent Pathways in Hepatoma Cells with Implications for Liver-Related Pathological Processes
title Sofosbuvir Activates EGFR-Dependent Pathways in Hepatoma Cells with Implications for Liver-Related Pathological Processes
title_full Sofosbuvir Activates EGFR-Dependent Pathways in Hepatoma Cells with Implications for Liver-Related Pathological Processes
title_fullStr Sofosbuvir Activates EGFR-Dependent Pathways in Hepatoma Cells with Implications for Liver-Related Pathological Processes
title_full_unstemmed Sofosbuvir Activates EGFR-Dependent Pathways in Hepatoma Cells with Implications for Liver-Related Pathological Processes
title_short Sofosbuvir Activates EGFR-Dependent Pathways in Hepatoma Cells with Implications for Liver-Related Pathological Processes
title_sort sofosbuvir activates egfr-dependent pathways in hepatoma cells with implications for liver-related pathological processes
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7225999/
https://www.ncbi.nlm.nih.gov/pubmed/32316635
http://dx.doi.org/10.3390/cells9041003
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