Autophagy-Related Chemoprotection against Sorafenib in Human Hepatocarcinoma: Role of FOXO3 Upregulation and Modulation by Regorafenib

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 pat...

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Autores principales:	Flavia Fondevila, Carolina Méndez-Blanco, Paula Fernández-Palanca, Tania Payo-Serafín, Jos van Pelt, Chris Verslype, Javier González-Gallego, José L. Mauriz
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	autophagy FOXO3 hepatocarcinoma regorafenib resistance sorafenib Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/720f30c47f404df2afd247b3f8bf4180
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spelling	oai:doaj.org-article:720f30c47f404df2afd247b3f8bf41802021-11-11T17:13:18ZAutophagy-Related Chemoprotection against Sorafenib in Human Hepatocarcinoma: Role of FOXO3 Upregulation and Modulation by Regorafenib10.3390/ijms2221117701422-00671661-6596https://doaj.org/article/720f30c47f404df2afd247b3f8bf41802021-10-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/11770https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Early 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.Flavia FondevilaCarolina Méndez-BlancoPaula Fernández-PalancaTania Payo-SerafínJos van PeltChris VerslypeJavier González-GallegoJosé L. MaurizMDPI AGarticleautophagyFOXO3hepatocarcinomaregorafenibresistancesorafenibBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 11770, p 11770 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	autophagy FOXO3 hepatocarcinoma regorafenib resistance sorafenib Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	autophagy FOXO3 hepatocarcinoma regorafenib resistance sorafenib Biology (General) QH301-705.5 Chemistry QD1-999 Flavia Fondevila Carolina Méndez-Blanco Paula Fernández-Palanca Tania Payo-Serafín Jos van Pelt Chris Verslype Javier González-Gallego José L. Mauriz Autophagy-Related Chemoprotection against Sorafenib in Human Hepatocarcinoma: Role of FOXO3 Upregulation and Modulation by Regorafenib
description	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.
format	article
author	Flavia Fondevila Carolina Méndez-Blanco Paula Fernández-Palanca Tania Payo-Serafín Jos van Pelt Chris Verslype Javier González-Gallego José L. Mauriz
author_facet	Flavia Fondevila Carolina Méndez-Blanco Paula Fernández-Palanca Tania Payo-Serafín Jos van Pelt Chris Verslype Javier González-Gallego José L. Mauriz
author_sort	Flavia Fondevila
title	Autophagy-Related Chemoprotection against Sorafenib in Human Hepatocarcinoma: Role of FOXO3 Upregulation and Modulation by Regorafenib
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
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/720f30c47f404df2afd247b3f8bf4180
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Autophagy-Related Chemoprotection against Sorafenib in Human Hepatocarcinoma: Role of FOXO3 Upregulation and Modulation by Regorafenib

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