Hepatocellular carcinoma cells loss lenvatinib efficacy in vitro through autophagy and hypoxia response-derived neuropilin-1 degradation

[EN] Despite pharmacological advances such as lenvatinib approval, therapeutic failure of hepatocellular carcinoma (HCC) remains a big challenge due to the complexity of its underlying molecular mechanisms. Neuropilin-1 (NRP1) is a co-receptor involved in several cellular processes associated to che...

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Autores: Fernández Palanca, Paula, Payo Serafín, Tania, San Miguel de Vega, Beatriz, Méndez Blanco, Carolina, Tuñón González, María Jesús, González Gallego, Javier, Mauriz Gutiérrez, José Luis
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2023
País:España
Institución:Universidad de León
Repositorio:BULERIA. Repositorio Institucional de la Universidad de León
OAI Identifier:oai:buleria.unileon.es:10612/23228
Acceso en línea:https://www.nature.com/articles/s41401-022-01021-2
https://hdl.handle.net/10612/23228
Access Level:acceso abierto
Palabra clave:Fisiología
Medicina. Salud
HIF-1α
autophagy
hepatocellular carcinoma cells
hypoxia
neuropilin-1
lenvatinib
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spelling Hepatocellular carcinoma cells loss lenvatinib efficacy in vitro through autophagy and hypoxia response-derived neuropilin-1 degradationFernández Palanca, PaulaPayo Serafín, TaniaSan Miguel de Vega, BeatrizMéndez Blanco, CarolinaTuñón González, María JesúsGonzález Gallego, JavierMauriz Gutiérrez, José LuisFisiologíaMedicina. SaludHIF-1αautophagyhepatocellular carcinoma cellshypoxianeuropilin-1lenvatinib[EN] Despite pharmacological advances such as lenvatinib approval, therapeutic failure of hepatocellular carcinoma (HCC) remains a big challenge due to the complexity of its underlying molecular mechanisms. Neuropilin-1 (NRP1) is a co-receptor involved in several cellular processes associated to chemoresistance development. Since both the double-edged process of autophagy and hypoxia-derived response play crucial roles in the loss of therapeutic effectiveness, herein we investigated the interplay among NRP1, autophagy and hypoxia in development of lenvatinib resistance in HCC cell lines. We first analyzed NRP1 expression levels in human HCC samples from public databases, found significantly increased NRP1 expression in human HCC samples as well as its correlation with advanced tumor and metastasis stages. Among 3 HCC cell lines (HepG2, Huh-7 and Hep3B), Hep3B and Huh-7 cells showed significantly increased NRP1 expression levels and cell migration ability together with higher susceptibility to lenvatinib. We demonstrated that NRP1 gene silencing significantly enhanced the anticancer effects of lenvatinib on Hep3B and Huh-7 cells. Furthermore, lenvatinib suppressed NRP1 expression through promoting autophagy in Hep3B and Huh-7 cells; co-treatment with bafilomycin A1 attenuated the antitumor effects of lenvatinib, and NRP1 silencing prevented this loss of in vitro effectiveness of lenvatinib even in the presence of bafilomycin A1. In addition, exposure to a hypoxic microenvironment significantly decreased NRP1 expression through autophagy in Hep3B and Huh-7 cells. Under hypoxia, HIF-1α directly modulated NRP1 expression; HIF-1α silencing not only enhanced the anticancer effects of combined lenvatinib and hypoxia, but also prevented the loss of effectiveness caused by bafilomycin A1, highlighting the potential role of HIF-1α-derived hypoxia response in the adaptive cellular response to lenvatinib and promoting resistance acquisition by autophagy modulation. Overall, NRP1 may constitute a potential therapeutic target to prevent lenvatinib failure derived from a hypoxia-associated modulation of autophagy in advanced HCC.SINature portfolioFisiologiaFacultad de Veterinaria2023info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://www.nature.com/articles/s41401-022-01021-2https://hdl.handle.net/10612/23228reponame:BULERIA. Repositorio Institucional de la Universidad de Leóninstname:Universidad de LeónIngléshttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:buleria.unileon.es:10612/232282026-06-24T12:43:27Z
dc.title.none.fl_str_mv Hepatocellular carcinoma cells loss lenvatinib efficacy in vitro through autophagy and hypoxia response-derived neuropilin-1 degradation
title Hepatocellular carcinoma cells loss lenvatinib efficacy in vitro through autophagy and hypoxia response-derived neuropilin-1 degradation
spellingShingle Hepatocellular carcinoma cells loss lenvatinib efficacy in vitro through autophagy and hypoxia response-derived neuropilin-1 degradation
Fernández Palanca, Paula
Fisiología
Medicina. Salud
HIF-1α
autophagy
hepatocellular carcinoma cells
hypoxia
neuropilin-1
lenvatinib
title_short Hepatocellular carcinoma cells loss lenvatinib efficacy in vitro through autophagy and hypoxia response-derived neuropilin-1 degradation
title_full Hepatocellular carcinoma cells loss lenvatinib efficacy in vitro through autophagy and hypoxia response-derived neuropilin-1 degradation
title_fullStr Hepatocellular carcinoma cells loss lenvatinib efficacy in vitro through autophagy and hypoxia response-derived neuropilin-1 degradation
title_full_unstemmed Hepatocellular carcinoma cells loss lenvatinib efficacy in vitro through autophagy and hypoxia response-derived neuropilin-1 degradation
title_sort Hepatocellular carcinoma cells loss lenvatinib efficacy in vitro through autophagy and hypoxia response-derived neuropilin-1 degradation
dc.creator.none.fl_str_mv Fernández Palanca, Paula
Payo Serafín, Tania
San Miguel de Vega, Beatriz
Méndez Blanco, Carolina
Tuñón González, María Jesús
González Gallego, Javier
Mauriz Gutiérrez, José Luis
author Fernández Palanca, Paula
author_facet Fernández Palanca, Paula
Payo Serafín, Tania
San Miguel de Vega, Beatriz
Méndez Blanco, Carolina
Tuñón González, María Jesús
González Gallego, Javier
Mauriz Gutiérrez, José Luis
author_role author
author2 Payo Serafín, Tania
San Miguel de Vega, Beatriz
Méndez Blanco, Carolina
Tuñón González, María Jesús
González Gallego, Javier
Mauriz Gutiérrez, José Luis
author2_role 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
HIF-1α
autophagy
hepatocellular carcinoma cells
hypoxia
neuropilin-1
lenvatinib
topic Fisiología
Medicina. Salud
HIF-1α
autophagy
hepatocellular carcinoma cells
hypoxia
neuropilin-1
lenvatinib
description [EN] Despite pharmacological advances such as lenvatinib approval, therapeutic failure of hepatocellular carcinoma (HCC) remains a big challenge due to the complexity of its underlying molecular mechanisms. Neuropilin-1 (NRP1) is a co-receptor involved in several cellular processes associated to chemoresistance development. Since both the double-edged process of autophagy and hypoxia-derived response play crucial roles in the loss of therapeutic effectiveness, herein we investigated the interplay among NRP1, autophagy and hypoxia in development of lenvatinib resistance in HCC cell lines. We first analyzed NRP1 expression levels in human HCC samples from public databases, found significantly increased NRP1 expression in human HCC samples as well as its correlation with advanced tumor and metastasis stages. Among 3 HCC cell lines (HepG2, Huh-7 and Hep3B), Hep3B and Huh-7 cells showed significantly increased NRP1 expression levels and cell migration ability together with higher susceptibility to lenvatinib. We demonstrated that NRP1 gene silencing significantly enhanced the anticancer effects of lenvatinib on Hep3B and Huh-7 cells. Furthermore, lenvatinib suppressed NRP1 expression through promoting autophagy in Hep3B and Huh-7 cells; co-treatment with bafilomycin A1 attenuated the antitumor effects of lenvatinib, and NRP1 silencing prevented this loss of in vitro effectiveness of lenvatinib even in the presence of bafilomycin A1. In addition, exposure to a hypoxic microenvironment significantly decreased NRP1 expression through autophagy in Hep3B and Huh-7 cells. Under hypoxia, HIF-1α directly modulated NRP1 expression; HIF-1α silencing not only enhanced the anticancer effects of combined lenvatinib and hypoxia, but also prevented the loss of effectiveness caused by bafilomycin A1, highlighting the potential role of HIF-1α-derived hypoxia response in the adaptive cellular response to lenvatinib and promoting resistance acquisition by autophagy modulation. Overall, NRP1 may constitute a potential therapeutic target to prevent lenvatinib failure derived from a hypoxia-associated modulation of autophagy in advanced HCC.
publishDate 2023
dc.date.none.fl_str_mv 2023
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.nature.com/articles/s41401-022-01021-2
https://hdl.handle.net/10612/23228
url https://www.nature.com/articles/s41401-022-01021-2
https://hdl.handle.net/10612/23228
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
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 Nature portfolio
publisher.none.fl_str_mv Nature portfolio
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
_version_ 1869407992482365440
score 15.811543

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