Autophagy-related chemoprotection against sorafenib in human hepatocarcinoma: role of FOXO3 upregulation and modulation by regorafenib

[EN] Early acquisition of sorafenib resistance is responsible for the dismal prognosis of advanced hepatocarcinoma (HCC). Autophagy, a catabolic process involved in liver homeostasis, has been associated with chemosensitivity modulation. Forkhead box O3 (FOXO3) is a transcription factor linked to HC...

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Autores: Fondevila Pena, Flavia, Méndez Blanco, Carolina, Fernández Palanca, Paula, Payo Serafín, Tania, van Pelt, Jos, Verslype, Chris, González Gallego, Javier, Mauriz Gutiérrez, José Luis
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2021
País:España
Institución:Universidad de León
Repositorio:BULERIA. Repositorio Institucional de la Universidad de León
OAI Identifier:oai:buleria.unileon.es:10612/23225
Acceso en línea:https://www.mdpi.com/1422-0067/22/21/11770
https://hdl.handle.net/10612/23225
Access Level:acceso abierto
Palabra clave:Fisiología
Medicina. Salud
FOXO3
autophagy
hepatocarcinoma
regorafenib
resistance
sorafenib
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oai_identifier_str oai:buleria.unileon.es:10612/23225
network_acronym_str ES
network_name_str España
repository_id_str
spelling Autophagy-related chemoprotection against sorafenib in human hepatocarcinoma: role of FOXO3 upregulation and modulation by regorafenibFondevila Pena, FlaviaMéndez Blanco, CarolinaFernández Palanca, PaulaPayo Serafín, Taniavan Pelt, JosVerslype, ChrisGonzález Gallego, JavierMauriz Gutiérrez, José LuisFisiologíaMedicina. SaludFOXO3autophagyhepatocarcinomaregorafenibresistancesorafenib[EN] Early acquisition of sorafenib resistance is responsible for the dismal prognosis of advanced hepatocarcinoma (HCC). Autophagy, a catabolic process involved in liver homeostasis, has been associated with chemosensitivity modulation. Forkhead box O3 (FOXO3) is a transcription factor linked to HCC pathogenesis whose role on autophagy-related sorafenib resistance remains controversial. Here, we unraveled the linkage between autophagy and sorafenib resistance in HCC, focusing on the implication of FOXO3 and its potential modulation by regorafenib. We worked with two HepG2-derived sorafenib-resistant HCC in vitro models (HepG2S1 and HepG2S3) and checked HCC patient data from the UALCAN database. Resistant cells displayed an enhanced basal autophagic flux compared to HepG2, showing higher autophagolysosome content and autophagy markers levels. Pharmacological inhibition of autophagy boosted HepG2S1 and HepG2S3 apoptosis and subG1 cells, but reduced viability, indicating the cytoprotective role of autophagy. HCC samples displayed higher FOXO3 levels, being associated with shorter survival and autophagic genes expression. Consistently, chemoresistant in vitro models showed significant FOXO3 upregulation. FOXO3 knockdown suppressed autophagy and caused resistant cell death, demonstrating that overactivation of such pro-survival autophagy during sorafenib resistance is FOXO3-dependent; a cytoprotective mechanism that the second-line drug regorafenib successfully abolished. Therefore, targeting FOXO3-mediated autophagy could significantly improve the clinical efficacy of sorafenib.SIMDPIFisiologiaFacultad de Veterinaria2021info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://www.mdpi.com/1422-0067/22/21/11770https://hdl.handle.net/10612/23225reponame:BULERIA. Repositorio Institucional de la Universidad de Leóninstname:Universidad de LeónEspañolhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:buleria.unileon.es:10612/232252026-06-24T12:43:27Z
dc.title.none.fl_str_mv Autophagy-related chemoprotection against sorafenib in human hepatocarcinoma: role of FOXO3 upregulation and modulation by regorafenib
title Autophagy-related chemoprotection against sorafenib in human hepatocarcinoma: role of FOXO3 upregulation and modulation by regorafenib
spellingShingle Autophagy-related chemoprotection against sorafenib in human hepatocarcinoma: role of FOXO3 upregulation and modulation by regorafenib
Fondevila Pena, Flavia
Fisiología
Medicina. Salud
FOXO3
autophagy
hepatocarcinoma
regorafenib
resistance
sorafenib
title_short Autophagy-related chemoprotection against sorafenib in human hepatocarcinoma: role of FOXO3 upregulation and modulation by regorafenib
title_full Autophagy-related chemoprotection against sorafenib in human hepatocarcinoma: role of FOXO3 upregulation and modulation by regorafenib
title_fullStr Autophagy-related chemoprotection against sorafenib in human hepatocarcinoma: role of FOXO3 upregulation and modulation by regorafenib
title_full_unstemmed Autophagy-related chemoprotection against sorafenib in human hepatocarcinoma: role of FOXO3 upregulation and modulation by regorafenib
title_sort Autophagy-related chemoprotection against sorafenib in human hepatocarcinoma: role of FOXO3 upregulation and modulation by regorafenib
dc.creator.none.fl_str_mv Fondevila Pena, Flavia
Méndez Blanco, Carolina
Fernández Palanca, Paula
Payo Serafín, Tania
van Pelt, Jos
Verslype, Chris
González Gallego, Javier
Mauriz Gutiérrez, José Luis
author Fondevila Pena, Flavia
author_facet Fondevila Pena, Flavia
Méndez Blanco, Carolina
Fernández Palanca, Paula
Payo Serafín, Tania
van Pelt, Jos
Verslype, Chris
González Gallego, Javier
Mauriz Gutiérrez, José Luis
author_role author
author2 Méndez Blanco, Carolina
Fernández Palanca, Paula
Payo Serafín, Tania
van Pelt, Jos
Verslype, Chris
González Gallego, Javier
Mauriz Gutiérrez, José Luis
author2_role author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Fisiologia
Facultad de Veterinaria
dc.subject.none.fl_str_mv Fisiología
Medicina. Salud
FOXO3
autophagy
hepatocarcinoma
regorafenib
resistance
sorafenib
topic Fisiología
Medicina. Salud
FOXO3
autophagy
hepatocarcinoma
regorafenib
resistance
sorafenib
description [EN] Early acquisition of sorafenib resistance is responsible for the dismal prognosis of advanced hepatocarcinoma (HCC). Autophagy, a catabolic process involved in liver homeostasis, has been associated with chemosensitivity modulation. Forkhead box O3 (FOXO3) is a transcription factor linked to HCC pathogenesis whose role on autophagy-related sorafenib resistance remains controversial. Here, we unraveled the linkage between autophagy and sorafenib resistance in HCC, focusing on the implication of FOXO3 and its potential modulation by regorafenib. We worked with two HepG2-derived sorafenib-resistant HCC in vitro models (HepG2S1 and HepG2S3) and checked HCC patient data from the UALCAN database. Resistant cells displayed an enhanced basal autophagic flux compared to HepG2, showing higher autophagolysosome content and autophagy markers levels. Pharmacological inhibition of autophagy boosted HepG2S1 and HepG2S3 apoptosis and subG1 cells, but reduced viability, indicating the cytoprotective role of autophagy. HCC samples displayed higher FOXO3 levels, being associated with shorter survival and autophagic genes expression. Consistently, chemoresistant in vitro models showed significant FOXO3 upregulation. FOXO3 knockdown suppressed autophagy and caused resistant cell death, demonstrating that overactivation of such pro-survival autophagy during sorafenib resistance is FOXO3-dependent; a cytoprotective mechanism that the second-line drug regorafenib successfully abolished. Therefore, targeting FOXO3-mediated autophagy could significantly improve the clinical efficacy of sorafenib.
publishDate 2021
dc.date.none.fl_str_mv 2021
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://www.mdpi.com/1422-0067/22/21/11770
https://hdl.handle.net/10612/23225
url https://www.mdpi.com/1422-0067/22/21/11770
https://hdl.handle.net/10612/23225
dc.language.none.fl_str_mv Español
language_invalid_str_mv Español
dc.rights.none.fl_str_mv http://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv MDPI
publisher.none.fl_str_mv MDPI
dc.source.none.fl_str_mv reponame:BULERIA. Repositorio Institucional de la Universidad de León
instname:Universidad de León
instname_str Universidad de León
reponame_str BULERIA. Repositorio Institucional de la Universidad de León
collection BULERIA. Repositorio Institucional de la Universidad de León
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812429

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