Involvement of both caspase-8 and Noxa-activated pathways in endoplasmic reticulum stress-induced apoptosis in triple-negative breast tumor cells

Recent evidences indicate that triple-negative breast cancer (TNBC) cells with a mesenchymal phenotype show a basal activation of the unfolded protein response (UPR) that increases their sensitivity to endoplasmic reticulum (ER) stress although the underlying cell death mechanism remains largely une...

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Detalhes bibliográficos
Autores: Cano-González, Ana, Mauro-Lizcano, Marta, Iglesias i Serret, Daniel, Gil i Santano, Joan, López Rivas, Abelardo
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2018
País:España
Recursos:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/121511
Acesso em linha:https://hdl.handle.net/2445/121511
Access Level:acceso abierto
Palavra-chave:Càncer de mama
Reticle endoplasmàtic
Apoptosi
Cèl·lules canceroses
Proteïnes
Breast cancer
Endoplasmic reticulum
Apoptosis
Cancer cells
Proteins
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repository_id_str
spelling Involvement of both caspase-8 and Noxa-activated pathways in endoplasmic reticulum stress-induced apoptosis in triple-negative breast tumor cellsCano-González, AnaMauro-Lizcano, MartaIglesias i Serret, DanielGil i Santano, JoanLópez Rivas, AbelardoCàncer de mamaReticle endoplasmàticApoptosiCèl·lules cancerosesProteïnesBreast cancerEndoplasmic reticulumApoptosisCancer cellsProteinsRecent evidences indicate that triple-negative breast cancer (TNBC) cells with a mesenchymal phenotype show a basal activation of the unfolded protein response (UPR) that increases their sensitivity to endoplasmic reticulum (ER) stress although the underlying cell death mechanism remains largely unexplored. Here we show that both caspase-8-dependent and -independent apoptotic mechanisms are activated in TNBC cells undergoing sustained ER stress. Activation of the extrinsic apoptotic pathway by ER stress involves ATF4-dependent upregulation of tumor necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAIL-R2/DR5). In addition, accumulation of BH3-only protein Noxa at the mitochondria further contributes to apoptosis following ER stress in TNBC cells. Accordingly, simultaneous abrogation of both extrinsic and intrinsic apoptotic pathways is required to inhibit ER stress-induced apoptosis in these cells. Importantly, persistent FLICE-inhibitory protein (FLIP) expression plays an adaptive role to prevent early activation of the extrinsic pathway of apoptosis upon ER stress. Overall, our data show that ER stress induces cell death through a pleiotropic mechanism in TNBC cells and suggest that targeting FLIP expression may be an effective approach to sensitize these tumor cells to ER stress-inducing agents.Nature Publishing Group2018info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/121511Articles publicats en revistes (Ciències Fisiològiques)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.1038/s41419-017-0164-7Cell Death and Disease, 2018, vol. 9, p. 134https://doi.org/10.1038/s41419-017-0164-7cc-by-nc-sa (c) Cano-González, Ana et al., 2018http://creativecommons.org/licenses/by-nc-sa/3.0/esinfo:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1215112026-05-27T06:46:51Z
dc.title.none.fl_str_mv Involvement of both caspase-8 and Noxa-activated pathways in endoplasmic reticulum stress-induced apoptosis in triple-negative breast tumor cells
title Involvement of both caspase-8 and Noxa-activated pathways in endoplasmic reticulum stress-induced apoptosis in triple-negative breast tumor cells
spellingShingle Involvement of both caspase-8 and Noxa-activated pathways in endoplasmic reticulum stress-induced apoptosis in triple-negative breast tumor cells
Cano-González, Ana
Càncer de mama
Reticle endoplasmàtic
Apoptosi
Cèl·lules canceroses
Proteïnes
Breast cancer
Endoplasmic reticulum
Apoptosis
Cancer cells
Proteins
title_short Involvement of both caspase-8 and Noxa-activated pathways in endoplasmic reticulum stress-induced apoptosis in triple-negative breast tumor cells
title_full Involvement of both caspase-8 and Noxa-activated pathways in endoplasmic reticulum stress-induced apoptosis in triple-negative breast tumor cells
title_fullStr Involvement of both caspase-8 and Noxa-activated pathways in endoplasmic reticulum stress-induced apoptosis in triple-negative breast tumor cells
title_full_unstemmed Involvement of both caspase-8 and Noxa-activated pathways in endoplasmic reticulum stress-induced apoptosis in triple-negative breast tumor cells
title_sort Involvement of both caspase-8 and Noxa-activated pathways in endoplasmic reticulum stress-induced apoptosis in triple-negative breast tumor cells
dc.creator.none.fl_str_mv Cano-González, Ana
Mauro-Lizcano, Marta
Iglesias i Serret, Daniel
Gil i Santano, Joan
López Rivas, Abelardo
author Cano-González, Ana
author_facet Cano-González, Ana
Mauro-Lizcano, Marta
Iglesias i Serret, Daniel
Gil i Santano, Joan
López Rivas, Abelardo
author_role author
author2 Mauro-Lizcano, Marta
Iglesias i Serret, Daniel
Gil i Santano, Joan
López Rivas, Abelardo
author2_role author
author
author
author
dc.subject.none.fl_str_mv Càncer de mama
Reticle endoplasmàtic
Apoptosi
Cèl·lules canceroses
Proteïnes
Breast cancer
Endoplasmic reticulum
Apoptosis
Cancer cells
Proteins
topic Càncer de mama
Reticle endoplasmàtic
Apoptosi
Cèl·lules canceroses
Proteïnes
Breast cancer
Endoplasmic reticulum
Apoptosis
Cancer cells
Proteins
description Recent evidences indicate that triple-negative breast cancer (TNBC) cells with a mesenchymal phenotype show a basal activation of the unfolded protein response (UPR) that increases their sensitivity to endoplasmic reticulum (ER) stress although the underlying cell death mechanism remains largely unexplored. Here we show that both caspase-8-dependent and -independent apoptotic mechanisms are activated in TNBC cells undergoing sustained ER stress. Activation of the extrinsic apoptotic pathway by ER stress involves ATF4-dependent upregulation of tumor necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAIL-R2/DR5). In addition, accumulation of BH3-only protein Noxa at the mitochondria further contributes to apoptosis following ER stress in TNBC cells. Accordingly, simultaneous abrogation of both extrinsic and intrinsic apoptotic pathways is required to inhibit ER stress-induced apoptosis in these cells. Importantly, persistent FLICE-inhibitory protein (FLIP) expression plays an adaptive role to prevent early activation of the extrinsic pathway of apoptosis upon ER stress. Overall, our data show that ER stress induces cell death through a pleiotropic mechanism in TNBC cells and suggest that targeting FLIP expression may be an effective approach to sensitize these tumor cells to ER stress-inducing agents.
publishDate 2018
dc.date.none.fl_str_mv 2018
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/2445/121511
url https://hdl.handle.net/2445/121511
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1038/s41419-017-0164-7
Cell Death and Disease, 2018, vol. 9, p. 134
https://doi.org/10.1038/s41419-017-0164-7
dc.rights.none.fl_str_mv cc-by-nc-sa (c) Cano-González, Ana et al., 2018
http://creativecommons.org/licenses/by-nc-sa/3.0/es
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by-nc-sa (c) Cano-González, Ana et al., 2018
http://creativecommons.org/licenses/by-nc-sa/3.0/es
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
dc.source.none.fl_str_mv Articles publicats en revistes (Ciències Fisiològiques)
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,300719

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