Sorafenib-associated translation reprogramming in hepatocellular carcinoma cells

Sorafenib (Sfb) is a multikinase inhibitor regularly used for the management of patients with advanced hepatocellular carcinoma (HCC) that has been shown to increase very modestly life expectancy. We have shown that Sfb inhibits protein synthesis at the level of initiation in cancer cells. However,...

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Autores: Contreras Bernal, Laura, Rodríguez Gil, Alfonso, Muntané Relat, Jordi, Cruz Díaz, Jesús de la
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2025
País:España
Institución:Universidad de Sevilla (US)
Repositorio:idUS. Depósito de Investigación de la Universidad de Sevilla
OAI Identifier:oai:idus.us.es:11441/172458
Acceso en línea:https://hdl.handle.net/11441/172458
https://doi.org/10.1080/15476286.2025.2483484
Access Level:acceso abierto
Palabra clave:Hepatocellular carcinoma
m6A methylation
Polysome profiling
Sorafenib
Translation
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spelling Sorafenib-associated translation reprogramming in hepatocellular carcinoma cellsContreras Bernal, LauraRodríguez Gil, AlfonsoMuntané Relat, JordiCruz Díaz, Jesús de laHepatocellular carcinomam6A methylationPolysome profilingSorafenibTranslationSorafenib (Sfb) is a multikinase inhibitor regularly used for the management of patients with advanced hepatocellular carcinoma (HCC) that has been shown to increase very modestly life expectancy. We have shown that Sfb inhibits protein synthesis at the level of initiation in cancer cells. However, the global snapshot of mRNA translation following Sorafenib-treatment has not been explored so far. In this study, we performed a genome-wide polysome profiling analysis in Sfb-treated HCC cells and demonstrated that, despite global translation repression, a set of different genes remain efficiently translated or are even translationally induced. We reveal that, in response to Sfb inhibition, translation is tuned, which strongly correlates with the presence of established mRNA cis-acting elements and the corresponding protein factors that recognize them, including DAP5 and ARE-binding proteins. At the level of biological processes, Sfb leads to the translational down-regulation of key cellular activities, such as those related to the mitochondrial metabolism and the collagen synthesis, and the translational up-regulation of pathways associated with the adaptation and survival of cells in response to the Sfb-induced stress. Our findings indicate that Sfb induces an adaptive reprogramming of translation and provides valuable information that can facilitate the analysis of other drugs for the development of novel combined treatment strategies based on Sfb therapy.Taylor and Francis Ltd.Fisiología Médica y BiofísicaGenéticaEuropean Cooperation in Science and TechnologyMinisterio de Ciencia e Innovación (MICIN). EspañaEuropean Commission (EC)Instituto de Salud Carlos IIIJunta de AndalucíaUniversidad de Sevilla2025info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttps://hdl.handle.net/11441/172458https://doi.org/10.1080/15476286.2025.2483484reponame:idUS. Depósito de Investigación de la Universidad de Sevillainstname:Universidad de Sevilla (US)InglésRNA Biology, 22 (1), 1-11.CA21154 TRANSLACOREPID2022-136564NB-I00FORT23/00008PI16/00090PI19/01266PI-0216–2000CB16/12/00480US-1380874https://doi.org/10.1080/15476286.2025.2483484info:eu-repo/semantics/openAccessoai:idus.us.es:11441/1724582026-06-17T12:51:07Z
dc.title.none.fl_str_mv Sorafenib-associated translation reprogramming in hepatocellular carcinoma cells
title Sorafenib-associated translation reprogramming in hepatocellular carcinoma cells
spellingShingle Sorafenib-associated translation reprogramming in hepatocellular carcinoma cells
Contreras Bernal, Laura
Hepatocellular carcinoma
m6A methylation
Polysome profiling
Sorafenib
Translation
title_short Sorafenib-associated translation reprogramming in hepatocellular carcinoma cells
title_full Sorafenib-associated translation reprogramming in hepatocellular carcinoma cells
title_fullStr Sorafenib-associated translation reprogramming in hepatocellular carcinoma cells
title_full_unstemmed Sorafenib-associated translation reprogramming in hepatocellular carcinoma cells
title_sort Sorafenib-associated translation reprogramming in hepatocellular carcinoma cells
dc.creator.none.fl_str_mv Contreras Bernal, Laura
Rodríguez Gil, Alfonso
Muntané Relat, Jordi
Cruz Díaz, Jesús de la
author Contreras Bernal, Laura
author_facet Contreras Bernal, Laura
Rodríguez Gil, Alfonso
Muntané Relat, Jordi
Cruz Díaz, Jesús de la
author_role author
author2 Rodríguez Gil, Alfonso
Muntané Relat, Jordi
Cruz Díaz, Jesús de la
author2_role author
author
author
dc.contributor.none.fl_str_mv Fisiología Médica y Biofísica
Genética
European Cooperation in Science and Technology
Ministerio de Ciencia e Innovación (MICIN). España
European Commission (EC)
Instituto de Salud Carlos III
Junta de Andalucía
Universidad de Sevilla
dc.subject.none.fl_str_mv Hepatocellular carcinoma
m6A methylation
Polysome profiling
Sorafenib
Translation
topic Hepatocellular carcinoma
m6A methylation
Polysome profiling
Sorafenib
Translation
description Sorafenib (Sfb) is a multikinase inhibitor regularly used for the management of patients with advanced hepatocellular carcinoma (HCC) that has been shown to increase very modestly life expectancy. We have shown that Sfb inhibits protein synthesis at the level of initiation in cancer cells. However, the global snapshot of mRNA translation following Sorafenib-treatment has not been explored so far. In this study, we performed a genome-wide polysome profiling analysis in Sfb-treated HCC cells and demonstrated that, despite global translation repression, a set of different genes remain efficiently translated or are even translationally induced. We reveal that, in response to Sfb inhibition, translation is tuned, which strongly correlates with the presence of established mRNA cis-acting elements and the corresponding protein factors that recognize them, including DAP5 and ARE-binding proteins. At the level of biological processes, Sfb leads to the translational down-regulation of key cellular activities, such as those related to the mitochondrial metabolism and the collagen synthesis, and the translational up-regulation of pathways associated with the adaptation and survival of cells in response to the Sfb-induced stress. Our findings indicate that Sfb induces an adaptive reprogramming of translation and provides valuable information that can facilitate the analysis of other drugs for the development of novel combined treatment strategies based on Sfb therapy.
publishDate 2025
dc.date.none.fl_str_mv 2025
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/11441/172458
https://doi.org/10.1080/15476286.2025.2483484
url https://hdl.handle.net/11441/172458
https://doi.org/10.1080/15476286.2025.2483484
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv RNA Biology, 22 (1), 1-11.
CA21154 TRANSLACORE
PID2022-136564NB-I00
FORT23/00008
PI16/00090
PI19/01266
PI-0216–2000
CB16/12/00480
US-1380874
https://doi.org/10.1080/15476286.2025.2483484
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Taylor and Francis Ltd.
publisher.none.fl_str_mv Taylor and Francis Ltd.
dc.source.none.fl_str_mv reponame:idUS. Depósito de Investigación de la Universidad de Sevilla
instname:Universidad de Sevilla (US)
instname_str Universidad de Sevilla (US)
reponame_str idUS. Depósito de Investigación de la Universidad de Sevilla
collection idUS. Depósito de Investigación de la Universidad de Sevilla
repository.name.fl_str_mv
repository.mail.fl_str_mv
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