Bortezomib initiates endoplasmic reticulum stress, elicits autophagy and death in echinococcus granulosus larval stage

Autores
Nicolao, María Celeste; Loos, Julia Alexandra; Rodríguez Rodrígues, Christian Fernando Ariel; Beas, Viviana; Cumino, Andrea Carina
Año de publicación
2017
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Cystic echinococcosis (CE) is a worldwide distributed helminthic zoonosis caused by Echinococcus granulosus. Benzimidazole derivatives are currently the only drugs for chemotherapeutic treatment of CE. However, their low efficacy and the adverse effects encourage the search for new therapeutic targets. We evaluated the in vitro efficacy of Bortezomib (Bz), a proteasome inhibitor, in the larval stage of the parasite. After 96 h, Bz showed potent deleterious effects at a concentration of 5 μM and 0.5 μM in protoscoleces and metacestodes, respectively (P < 0.05). After 48 h of exposure to this drug, it was triggered a mRNA overex-pression of chaperones (Eg-grp78 and Eg-calnexin) and of Eg-ire2/Eg-xbp1 (the conserved UPR pathway branch) in protoscoleces. No changes were detected in the transcriptional expression of chaperones in Bz-treated metacestodes, thus allowing ER stress to be evident and viability to highly decrease in comparison with protoscoleces. We also found that Bz treatment activated the autophagic process in both larval forms. These facts were evidenced by the increase in the amount of transcripts of the autophagy related genes (Eg-atg6, Eg-atg8, Eg-atg12, Eg-atg16) together with the increase in Eg-Atg8-II detected by western blot and by in toto immunofluorescence labeling. It was further confirmed by direct observation of autophagic structures by electronic microscopy. Finally, in order to determine the impact of autophagy induction on Echinococcus cell viability, we evaluated the efficacy of Bz in combination with rapamycin and a synergistic cytotoxic effect on protoscolex viability was observed when both drugs were used together. In conclusion, our findings demonstrated that Bz induced endoplasmic reticulum stress, autophagy and subsequent death allowing to identify unstudied parasite-host pathways that could provide a new insight for control of parasitic diseases.
Fil: Nicolao, María Celeste. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Loos, Julia Alexandra. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Rodríguez Rodrígues, Christian Fernando Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Mar del Plata; Argentina
Fil: Beas, Viviana. Hospital Privado de Comunidad; Argentina. Universidad Nacional de Mar del Plata; Argentina
Fil: Cumino, Andrea Carina. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Materia
echinococcus granulosus
bortezomib
endoplasmic reticulum stress
autophagy
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/72778
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/72778
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Bortezomib initiates endoplasmic reticulum stress, elicits autophagy and death in echinococcus granulosus larval stageNicolao, María CelesteLoos, Julia AlexandraRodríguez Rodrígues, Christian Fernando ArielBeas, VivianaCumino, Andrea Carinaechinococcus granulosusbortezomibendoplasmic reticulum stressautophagyhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Cystic echinococcosis (CE) is a worldwide distributed helminthic zoonosis caused by Echinococcus granulosus. Benzimidazole derivatives are currently the only drugs for chemotherapeutic treatment of CE. However, their low efficacy and the adverse effects encourage the search for new therapeutic targets. We evaluated the in vitro efficacy of Bortezomib (Bz), a proteasome inhibitor, in the larval stage of the parasite. After 96 h, Bz showed potent deleterious effects at a concentration of 5 μM and 0.5 μM in protoscoleces and metacestodes, respectively (P < 0.05). After 48 h of exposure to this drug, it was triggered a mRNA overex-pression of chaperones (Eg-grp78 and Eg-calnexin) and of Eg-ire2/Eg-xbp1 (the conserved UPR pathway branch) in protoscoleces. No changes were detected in the transcriptional expression of chaperones in Bz-treated metacestodes, thus allowing ER stress to be evident and viability to highly decrease in comparison with protoscoleces. We also found that Bz treatment activated the autophagic process in both larval forms. These facts were evidenced by the increase in the amount of transcripts of the autophagy related genes (Eg-atg6, Eg-atg8, Eg-atg12, Eg-atg16) together with the increase in Eg-Atg8-II detected by western blot and by in toto immunofluorescence labeling. It was further confirmed by direct observation of autophagic structures by electronic microscopy. Finally, in order to determine the impact of autophagy induction on Echinococcus cell viability, we evaluated the efficacy of Bz in combination with rapamycin and a synergistic cytotoxic effect on protoscolex viability was observed when both drugs were used together. In conclusion, our findings demonstrated that Bz induced endoplasmic reticulum stress, autophagy and subsequent death allowing to identify unstudied parasite-host pathways that could provide a new insight for control of parasitic diseases.Fil: Nicolao, María Celeste. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Loos, Julia Alexandra. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Rodríguez Rodrígues, Christian Fernando Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Mar del Plata; ArgentinaFil: Beas, Viviana. Hospital Privado de Comunidad; Argentina. Universidad Nacional de Mar del Plata; ArgentinaFil: Cumino, Andrea Carina. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaPublic Library of Science2017-08info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/72778Nicolao, María Celeste; Loos, Julia Alexandra; Rodríguez Rodrígues, Christian Fernando Ariel; Beas, Viviana; Cumino, Andrea Carina; Bortezomib initiates endoplasmic reticulum stress, elicits autophagy and death in echinococcus granulosus larval stage; Public Library of Science; Plos One; 12; 8; 8-2017; 1-19; e01815281932-6203CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1371/journal.pone.0181528info:eu-repo/semantics/altIdentifier/url/https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0181528info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:10:42Zoai:ri.conicet.gov.ar:11336/72778instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 10:10:42.477CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Bortezomib initiates endoplasmic reticulum stress, elicits autophagy and death in echinococcus granulosus larval stage
title Bortezomib initiates endoplasmic reticulum stress, elicits autophagy and death in echinococcus granulosus larval stage
spellingShingle Bortezomib initiates endoplasmic reticulum stress, elicits autophagy and death in echinococcus granulosus larval stage
Nicolao, María Celeste
echinococcus granulosus
bortezomib
endoplasmic reticulum stress
autophagy
title_short Bortezomib initiates endoplasmic reticulum stress, elicits autophagy and death in echinococcus granulosus larval stage
title_full Bortezomib initiates endoplasmic reticulum stress, elicits autophagy and death in echinococcus granulosus larval stage
title_fullStr Bortezomib initiates endoplasmic reticulum stress, elicits autophagy and death in echinococcus granulosus larval stage
title_full_unstemmed Bortezomib initiates endoplasmic reticulum stress, elicits autophagy and death in echinococcus granulosus larval stage
title_sort Bortezomib initiates endoplasmic reticulum stress, elicits autophagy and death in echinococcus granulosus larval stage
dc.creator.none.fl_str_mv Nicolao, María Celeste
Loos, Julia Alexandra
Rodríguez Rodrígues, Christian Fernando Ariel
Beas, Viviana
Cumino, Andrea Carina
author Nicolao, María Celeste
author_facet Nicolao, María Celeste
Loos, Julia Alexandra
Rodríguez Rodrígues, Christian Fernando Ariel
Beas, Viviana
Cumino, Andrea Carina
author_role author
author2 Loos, Julia Alexandra
Rodríguez Rodrígues, Christian Fernando Ariel
Beas, Viviana
Cumino, Andrea Carina
author2_role author
author
author
author
dc.subject.none.fl_str_mv echinococcus granulosus
bortezomib
endoplasmic reticulum stress
autophagy
topic echinococcus granulosus
bortezomib
endoplasmic reticulum stress
autophagy
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Cystic echinococcosis (CE) is a worldwide distributed helminthic zoonosis caused by Echinococcus granulosus. Benzimidazole derivatives are currently the only drugs for chemotherapeutic treatment of CE. However, their low efficacy and the adverse effects encourage the search for new therapeutic targets. We evaluated the in vitro efficacy of Bortezomib (Bz), a proteasome inhibitor, in the larval stage of the parasite. After 96 h, Bz showed potent deleterious effects at a concentration of 5 μM and 0.5 μM in protoscoleces and metacestodes, respectively (P < 0.05). After 48 h of exposure to this drug, it was triggered a mRNA overex-pression of chaperones (Eg-grp78 and Eg-calnexin) and of Eg-ire2/Eg-xbp1 (the conserved UPR pathway branch) in protoscoleces. No changes were detected in the transcriptional expression of chaperones in Bz-treated metacestodes, thus allowing ER stress to be evident and viability to highly decrease in comparison with protoscoleces. We also found that Bz treatment activated the autophagic process in both larval forms. These facts were evidenced by the increase in the amount of transcripts of the autophagy related genes (Eg-atg6, Eg-atg8, Eg-atg12, Eg-atg16) together with the increase in Eg-Atg8-II detected by western blot and by in toto immunofluorescence labeling. It was further confirmed by direct observation of autophagic structures by electronic microscopy. Finally, in order to determine the impact of autophagy induction on Echinococcus cell viability, we evaluated the efficacy of Bz in combination with rapamycin and a synergistic cytotoxic effect on protoscolex viability was observed when both drugs were used together. In conclusion, our findings demonstrated that Bz induced endoplasmic reticulum stress, autophagy and subsequent death allowing to identify unstudied parasite-host pathways that could provide a new insight for control of parasitic diseases.
Fil: Nicolao, María Celeste. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Loos, Julia Alexandra. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Rodríguez Rodrígues, Christian Fernando Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Mar del Plata; Argentina
Fil: Beas, Viviana. Hospital Privado de Comunidad; Argentina. Universidad Nacional de Mar del Plata; Argentina
Fil: Cumino, Andrea Carina. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
description Cystic echinococcosis (CE) is a worldwide distributed helminthic zoonosis caused by Echinococcus granulosus. Benzimidazole derivatives are currently the only drugs for chemotherapeutic treatment of CE. However, their low efficacy and the adverse effects encourage the search for new therapeutic targets. We evaluated the in vitro efficacy of Bortezomib (Bz), a proteasome inhibitor, in the larval stage of the parasite. After 96 h, Bz showed potent deleterious effects at a concentration of 5 μM and 0.5 μM in protoscoleces and metacestodes, respectively (P < 0.05). After 48 h of exposure to this drug, it was triggered a mRNA overex-pression of chaperones (Eg-grp78 and Eg-calnexin) and of Eg-ire2/Eg-xbp1 (the conserved UPR pathway branch) in protoscoleces. No changes were detected in the transcriptional expression of chaperones in Bz-treated metacestodes, thus allowing ER stress to be evident and viability to highly decrease in comparison with protoscoleces. We also found that Bz treatment activated the autophagic process in both larval forms. These facts were evidenced by the increase in the amount of transcripts of the autophagy related genes (Eg-atg6, Eg-atg8, Eg-atg12, Eg-atg16) together with the increase in Eg-Atg8-II detected by western blot and by in toto immunofluorescence labeling. It was further confirmed by direct observation of autophagic structures by electronic microscopy. Finally, in order to determine the impact of autophagy induction on Echinococcus cell viability, we evaluated the efficacy of Bz in combination with rapamycin and a synergistic cytotoxic effect on protoscolex viability was observed when both drugs were used together. In conclusion, our findings demonstrated that Bz induced endoplasmic reticulum stress, autophagy and subsequent death allowing to identify unstudied parasite-host pathways that could provide a new insight for control of parasitic diseases.
publishDate 2017
dc.date.none.fl_str_mv 2017-08
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/72778
Nicolao, María Celeste; Loos, Julia Alexandra; Rodríguez Rodrígues, Christian Fernando Ariel; Beas, Viviana; Cumino, Andrea Carina; Bortezomib initiates endoplasmic reticulum stress, elicits autophagy and death in echinococcus granulosus larval stage; Public Library of Science; Plos One; 12; 8; 8-2017; 1-19; e0181528
1932-6203
CONICET Digital
CONICET
url http://hdl.handle.net/11336/72778
identifier_str_mv Nicolao, María Celeste; Loos, Julia Alexandra; Rodríguez Rodrígues, Christian Fernando Ariel; Beas, Viviana; Cumino, Andrea Carina; Bortezomib initiates endoplasmic reticulum stress, elicits autophagy and death in echinococcus granulosus larval stage; Public Library of Science; Plos One; 12; 8; 8-2017; 1-19; e0181528
1932-6203
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1371/journal.pone.0181528
info:eu-repo/semantics/altIdentifier/url/https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0181528
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Public Library of Science
publisher.none.fl_str_mv Public Library of Science
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.070432

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