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Cells . 2020 Apr 17

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

Evangelos J Giamarellos-Bourboulis, Mihai G Netea, Nikoletta Rovina, Karolina Akinosoglou, Anastasia Antoniadou, Nikolaos Antonakos, Georgia Damoraki, Theologia Gkavogianni, Maria-Evangelia Adami, Paraskevi Katsaounou, Maria Ntaganou, Magdalini Kyriakopoulou, George Dimopoulos, Ioannis Koutsodimitropoulos, Dimitrios Velissaris, Panagiotis Koufargyris, Athanassios Karageorgos, Konstantina Katrini, Vasileios Lekakis, Mihaela Lupse, Antigone Kotsaki, George Renieris, Danai Theodoulou, Vassiliki Panou, Evangelia Koukaki, Nikolaos Koulouris, Charalambos Gogos, Antonia Koutsoukou, Samuel T Keating, Laszlo Groh, Charlotte D C C van der Heijden, Hanah Rodriguez, Jéssica C Dos Santos, Stephanie Fanucchi, Jun Okabe, Harikrishnan Kaipananickal, Jelmer H van Puffelen, Leonie Helder, Marlies P Noz, Vasiliki Matzaraki, Yang Li, L Charlotte J de Bree, Valerie A C M Koeken, Simone J C F M Moorlag, Vera P Mourits, Jorge Domínguez-Andrés, Marije Oosting, Elianne P Bulthuis, Werner J H Koopman, Musa Mhlanga, Assam El-Osta, Leo A B Joosten, Mihai G Netea, Niels P Riksen, Yushi Hayashi, Hidenori Suzuki, Wataru Nakajima, Ikuno Uehara, Atsuko Tanimura, Toshiki Himeda, Satoshi Koike, Tatsuya Katsuno, Shin-Ichiro Kitajiri, Naoto Koyanagi, Yasushi Kawaguchi, Koji Onomoto, Hiroki Kato, Mitsutoshi Yoneyama, Takashi Fujita, Nobuyuki Tanaka, Denisa Bojkova, Sandra Westhaus, Rui Costa, Lejla Timmer, Nora Funkenberg, Marek Korencak, Hendrik Streeck, Florian Vondran, Ruth Broering, Stefan Heinrichs, Karl S Lang, Sandra Ciesek

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.

PMID: 32316635