Aripiprazole cytotoxicity coincides with activation of the unfolded protein response in human hepatic cells

Schizophrenia is a mental disease that results in decreased life expectancy and wellbeing, by promoting obesity and sedentary lifestyles. Schizophrenia is treated by antipsychotic drugs. While the second generation of antipsychotics (SGA), Olanzapine and Aripiprazole are more effective in treating s...

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Autores: Forno, Francesca, Maatuf, Yossi, Boukeileh, Shatha, Dipta, Priya, Mahameed, Mohamed, Darawshi, Odai, Ferreira, Vítor, Rada, Patricia, García Martínez, Irma, Gross, Einav, Priel, Avi, Valverde, Ángela M., Tirosh, Boaz
Tipo de documento: artigo
Estado:Versión aceptada para publicación
Data de publicação:2020
País:España
Recursos:Consejo Superior de Investigaciones Científicas (CSIC)
Repositório:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/222081
Acesso em linha:http://hdl.handle.net/10261/222081
Access Level:Acceso aberto
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spelling Aripiprazole cytotoxicity coincides with activation of the unfolded protein response in human hepatic cellsForno, FrancescaMaatuf, YossiBoukeileh, ShathaDipta, PriyaMahameed, MohamedDarawshi, OdaiFerreira, VítorRada, PatriciaGarcía Martínez, IrmaGross, EinavPriel, AviValverde, Ángela M.Tirosh, BoazSchizophrenia is a mental disease that results in decreased life expectancy and wellbeing, by promoting obesity and sedentary lifestyles. Schizophrenia is treated by antipsychotic drugs. While the second generation of antipsychotics (SGA), Olanzapine and Aripiprazole are more effective in treating schizophrenia, they display a higher risk of metabolic side effects, mostly by development of diabetes and insulin resistance, weight gain as well as dyslipidemia. Endoplasmic reticulum (ER) stress is induced when ER homeostasis of lipid biosynthesis and protein folding is impaired. This leads to the activation of the unfolded protein response (UPR), a signaling cascade that aims to restore ER homeostasis or initiate cell death. Chronic conditions of ER stress in the liver are associated with diabetes and perturbed lipid metabolism. These metabolic dysfunctions resemble the pharmacological side effects of SGAs. We, therefore, investigated whether SGAs promote the UPR in human and mouse hepatocytes. We observed full-fledged activation of ER stress by Aripiprazole, not by Olanzapine. This occurred at low micromolar concentrations and to variable intensities in different cell types, such as hepatocellular carcinoma, melanoma and glioblastoma. Mechanistically, Aripiprazole caused depletion of ER calcium, leading to activation of IRE1 and PERK, two major transducers of the UPR. Cells underwent apoptosis upon Aripiprazole treatment, which coincided with UPR induction, and this effect was reduced by adding glutathione without affecting UPR itself. Deletion of IRE1 from HepG2 cells protected cells from Aripiprazole toxicity. Our study reveals for the first time a cytotoxic effect of Aripiprazole that involves the induction of ER stress.FF, PD and VF are Marie Curie fellows [Treatment H2020-MSCA-ITN721236]. AMV, PR and IGM were supported by grants [RTI2018-094052-B-100] (MCIU/AEI/FEDER, UE)) and [S2017/BMD-3684] MOIR2-CM (Comunidad de Madrid, Spain) and CIBERdem (ISCIII, Spain).Peer reviewedAmerican Society for Pharmacology and Experimental TherapeuticsEuropean CommissionAgencia Estatal de Investigación (España)Ministerio de Ciencia, Innovación y Universidades (España)Comunidad de MadridInstituto de Salud Carlos IIIConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202020202020info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Postprintinfo:eu-repo/semantics/acceptedVersionhttp://hdl.handle.net/10261/222081reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/EC/H2020/721236info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RTI2018-094052-B-100RTI2018-094052-B-100/AEI/10.13039/501100011033S2017/BMD-3684/MOIR2-CMForno, Francesca; Maatuf, Yossi; Boukeileh, Shatha; Dipta, Priya; Mahameed, Mohamed; Darawshi, Odai; Ferreira, Vítor; Rada, Patricia; García Martínez, Irma; Gross, Einav; Priel, Avi; Valverde, Ángela M.; Tirosh, Boaz. (2020): "Dataset related to article: Aripiprazole cytotoxicity coincides with activation of the unfolded protein response in human hepatic cells [Dataset]", http://dx.doi.org/10.20350/digitalCSIC/13925https://doi.org/10.1124/jpet.119.264481Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2220812026-05-22T06:33:51Z
dc.title.none.fl_str_mv Aripiprazole cytotoxicity coincides with activation of the unfolded protein response in human hepatic cells
title Aripiprazole cytotoxicity coincides with activation of the unfolded protein response in human hepatic cells
spellingShingle Aripiprazole cytotoxicity coincides with activation of the unfolded protein response in human hepatic cells
Forno, Francesca
title_short Aripiprazole cytotoxicity coincides with activation of the unfolded protein response in human hepatic cells
title_full Aripiprazole cytotoxicity coincides with activation of the unfolded protein response in human hepatic cells
title_fullStr Aripiprazole cytotoxicity coincides with activation of the unfolded protein response in human hepatic cells
title_full_unstemmed Aripiprazole cytotoxicity coincides with activation of the unfolded protein response in human hepatic cells
title_sort Aripiprazole cytotoxicity coincides with activation of the unfolded protein response in human hepatic cells
dc.creator.none.fl_str_mv Forno, Francesca
Maatuf, Yossi
Boukeileh, Shatha
Dipta, Priya
Mahameed, Mohamed
Darawshi, Odai
Ferreira, Vítor
Rada, Patricia
García Martínez, Irma
Gross, Einav
Priel, Avi
Valverde, Ángela M.
Tirosh, Boaz
author Forno, Francesca
author_facet Forno, Francesca
Maatuf, Yossi
Boukeileh, Shatha
Dipta, Priya
Mahameed, Mohamed
Darawshi, Odai
Ferreira, Vítor
Rada, Patricia
García Martínez, Irma
Gross, Einav
Priel, Avi
Valverde, Ángela M.
Tirosh, Boaz
author_role author
author2 Maatuf, Yossi
Boukeileh, Shatha
Dipta, Priya
Mahameed, Mohamed
Darawshi, Odai
Ferreira, Vítor
Rada, Patricia
García Martínez, Irma
Gross, Einav
Priel, Avi
Valverde, Ángela M.
Tirosh, Boaz
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv European Commission
Agencia Estatal de Investigación (España)
Ministerio de Ciencia, Innovación y Universidades (España)
Comunidad de Madrid
Instituto de Salud Carlos III
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
description Schizophrenia is a mental disease that results in decreased life expectancy and wellbeing, by promoting obesity and sedentary lifestyles. Schizophrenia is treated by antipsychotic drugs. While the second generation of antipsychotics (SGA), Olanzapine and Aripiprazole are more effective in treating schizophrenia, they display a higher risk of metabolic side effects, mostly by development of diabetes and insulin resistance, weight gain as well as dyslipidemia. Endoplasmic reticulum (ER) stress is induced when ER homeostasis of lipid biosynthesis and protein folding is impaired. This leads to the activation of the unfolded protein response (UPR), a signaling cascade that aims to restore ER homeostasis or initiate cell death. Chronic conditions of ER stress in the liver are associated with diabetes and perturbed lipid metabolism. These metabolic dysfunctions resemble the pharmacological side effects of SGAs. We, therefore, investigated whether SGAs promote the UPR in human and mouse hepatocytes. We observed full-fledged activation of ER stress by Aripiprazole, not by Olanzapine. This occurred at low micromolar concentrations and to variable intensities in different cell types, such as hepatocellular carcinoma, melanoma and glioblastoma. Mechanistically, Aripiprazole caused depletion of ER calcium, leading to activation of IRE1 and PERK, two major transducers of the UPR. Cells underwent apoptosis upon Aripiprazole treatment, which coincided with UPR induction, and this effect was reduced by adding glutathione without affecting UPR itself. Deletion of IRE1 from HepG2 cells protected cells from Aripiprazole toxicity. Our study reveals for the first time a cytotoxic effect of Aripiprazole that involves the induction of ER stress.
publishDate 2020
dc.date.none.fl_str_mv 2020
2020
2020
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Postprint
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/222081
url http://hdl.handle.net/10261/222081
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/EC/H2020/721236
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RTI2018-094052-B-100
RTI2018-094052-B-100/AEI/10.13039/501100011033
S2017/BMD-3684/MOIR2-CM
Forno, Francesca; Maatuf, Yossi; Boukeileh, Shatha; Dipta, Priya; Mahameed, Mohamed; Darawshi, Odai; Ferreira, Vítor; Rada, Patricia; García Martínez, Irma; Gross, Einav; Priel, Avi; Valverde, Ángela M.; Tirosh, Boaz. (2020): "Dataset related to article: Aripiprazole cytotoxicity coincides with activation of the unfolded protein response in human hepatic cells [Dataset]", http://dx.doi.org/10.20350/digitalCSIC/13925
https://doi.org/10.1124/jpet.119.264481
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv American Society for Pharmacology and Experimental Therapeutics
publisher.none.fl_str_mv American Society for Pharmacology and Experimental Therapeutics
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
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