Mifepristone increases mRNA translation rate, triggers the unfolded protein response, increases autophagic flux, and kills ovarian cancer cells in combination with proteasome or ly...

Autores
Zhang, Lei; Hapon, María Belén; Goyeneche, Alicia A.; Srinivasan, Rekha; Gamarra Luques, Carlos Diego; Callegari, Eduardo A.; Drappeau, Donis D.; Terpstra, Erin J.; Pan, Bo; Knapp, Jennifer R.; Chien, Jeremy; Wang, Xuejun; Eyster, Kathleen M.; Telleria, Carlos Marcelo
Año de publicación
2016
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
The synthetic steroid mifepristone blocks the growth of ovarian cancer cells, yet the mechanism driving such effect is not entirely understood. Unbiased genomic and proteomic screenings using ovarian cancer cell lines of different genetic backgrounds and sensitivities to platinum led to the identification of two key genes upregulated by mifepristone and involved in the unfolded protein response (UPR): the master chaperone of the endoplasmic reticulum (ER), glucose regulated protein (GRP) of 78 kDa, and the CCAAT/enhancer binding protein homologous transcription factor (CHOP). GRP78 and CHOP were upregulated by mifepristone in ovarian cancer cells regardless of p53 status and platinum sensitivity. Further studies revealed that the three UPR-associated pathways, PERK, IRE1α, and ATF6, were activated by mifepristone. Also, the synthetic steroid acutely increased mRNA translation rate, which, if prevented, abrogated the splicing of XBP1 mRNA, a non-translatable readout of IRE1α activation. Moreover, mifepristone increased LC3-II levels due to increased autophagic flux. When the autophagic–lysosomal pathway was inhibited with chloroquine, mifepristone was lethal to the cells. Lastly, doses of proteasome inhibitors that are inadequate to block the activity of the proteasomes, caused cell death when combined with mifepristone; this phenotype was accompanied by accumulation of poly-ubiquitinated proteins denoting proteasome inhibition. The stimulation by mifepristone of ER stress and autophagic flux offers a therapeutic opportunity for utilizing this compound to sensitize ovarian cancer cells to proteasome or lysosome inhibitors.
Fil: Zhang, Lei. University Of South Dakota; Estados Unidos
Fil: Hapon, María Belén. University Of South Dakota; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina
Fil: Goyeneche, Alicia A.. University Of South Dakota; Estados Unidos. McGill University; Canadá
Fil: Srinivasan, Rekha. University Of South Dakota; Estados Unidos
Fil: Gamarra Luques, Carlos Diego. University Of South Dakota; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina
Fil: Callegari, Eduardo A.. University Of South Dakota; Estados Unidos
Fil: Drappeau, Donis D.. University Of South Dakota; Estados Unidos
Fil: Terpstra, Erin J.. University Of South Dakota; Estados Unidos
Fil: Pan, Bo. University Of South Dakota; Estados Unidos
Fil: Knapp, Jennifer R.. University of Kansas; Estados Unidos
Fil: Chien, Jeremy. University of Kansas; Estados Unidos
Fil: Wang, Xuejun. University Of South Dakota; Estados Unidos
Fil: Eyster, Kathleen M.. University Of South Dakota; Estados Unidos
Fil: Telleria, Carlos Marcelo. University Of South Dakota; Estados Unidos. McGill University; Canadá. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Materia
Autophagic Flux
Bortezomib
Chloroquine
Er Stress
Mifepristone
Mrna Translation
Ovarian Cancer
Ubiquitin Proteasome System
Unfolded Protein Response
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:11336/49777
Acceder
id CONICETDig_900fdf4788e981bef2c281ca45a50918
oai_identifier_str oai:ri.conicet.gov.ar:11336/49777
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Mifepristone increases mRNA translation rate, triggers the unfolded protein response, increases autophagic flux, and kills ovarian cancer cells in combination with proteasome or lysosome inhibitorsZhang, LeiHapon, María BelénGoyeneche, Alicia A.Srinivasan, RekhaGamarra Luques, Carlos DiegoCallegari, Eduardo A.Drappeau, Donis D.Terpstra, Erin J.Pan, BoKnapp, Jennifer R.Chien, JeremyWang, XuejunEyster, Kathleen M.Telleria, Carlos MarceloAutophagic FluxBortezomibChloroquineEr StressMifepristoneMrna TranslationOvarian CancerUbiquitin Proteasome SystemUnfolded Protein Responsehttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3The synthetic steroid mifepristone blocks the growth of ovarian cancer cells, yet the mechanism driving such effect is not entirely understood. Unbiased genomic and proteomic screenings using ovarian cancer cell lines of different genetic backgrounds and sensitivities to platinum led to the identification of two key genes upregulated by mifepristone and involved in the unfolded protein response (UPR): the master chaperone of the endoplasmic reticulum (ER), glucose regulated protein (GRP) of 78 kDa, and the CCAAT/enhancer binding protein homologous transcription factor (CHOP). GRP78 and CHOP were upregulated by mifepristone in ovarian cancer cells regardless of p53 status and platinum sensitivity. Further studies revealed that the three UPR-associated pathways, PERK, IRE1α, and ATF6, were activated by mifepristone. Also, the synthetic steroid acutely increased mRNA translation rate, which, if prevented, abrogated the splicing of XBP1 mRNA, a non-translatable readout of IRE1α activation. Moreover, mifepristone increased LC3-II levels due to increased autophagic flux. When the autophagic–lysosomal pathway was inhibited with chloroquine, mifepristone was lethal to the cells. Lastly, doses of proteasome inhibitors that are inadequate to block the activity of the proteasomes, caused cell death when combined with mifepristone; this phenotype was accompanied by accumulation of poly-ubiquitinated proteins denoting proteasome inhibition. The stimulation by mifepristone of ER stress and autophagic flux offers a therapeutic opportunity for utilizing this compound to sensitize ovarian cancer cells to proteasome or lysosome inhibitors.Fil: Zhang, Lei. University Of South Dakota; Estados UnidosFil: Hapon, María Belén. University Of South Dakota; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Goyeneche, Alicia A.. University Of South Dakota; Estados Unidos. McGill University; CanadáFil: Srinivasan, Rekha. University Of South Dakota; Estados UnidosFil: Gamarra Luques, Carlos Diego. University Of South Dakota; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Callegari, Eduardo A.. University Of South Dakota; Estados UnidosFil: Drappeau, Donis D.. University Of South Dakota; Estados UnidosFil: Terpstra, Erin J.. University Of South Dakota; Estados UnidosFil: Pan, Bo. University Of South Dakota; Estados UnidosFil: Knapp, Jennifer R.. University of Kansas; Estados UnidosFil: Chien, Jeremy. University of Kansas; Estados UnidosFil: Wang, Xuejun. University Of South Dakota; Estados UnidosFil: Eyster, Kathleen M.. University Of South Dakota; Estados UnidosFil: Telleria, Carlos Marcelo. University Of South Dakota; Estados Unidos. McGill University; Canadá. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaElsevier2016-08info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/49777Zhang, Lei; Hapon, María Belén; Goyeneche, Alicia A.; Srinivasan, Rekha; Gamarra Luques, Carlos Diego; et al.; Mifepristone increases mRNA translation rate, triggers the unfolded protein response, increases autophagic flux, and kills ovarian cancer cells in combination with proteasome or lysosome inhibitors; Elsevier; Molecular Oncology; 10; 7; 8-2016; 1099-11171574-7891CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1016/j.molonc.2016.05.001info:eu-repo/semantics/altIdentifier/url/https://febs.onlinelibrary.wiley.com/doi/abs/10.1016/j.molonc.2016.05.001info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:51:50Zoai:ri.conicet.gov.ar:11336/49777instacron: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:34982025-09-03 09:51:51.288CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Mifepristone increases mRNA translation rate, triggers the unfolded protein response, increases autophagic flux, and kills ovarian cancer cells in combination with proteasome or lysosome inhibitors
title Mifepristone increases mRNA translation rate, triggers the unfolded protein response, increases autophagic flux, and kills ovarian cancer cells in combination with proteasome or lysosome inhibitors
spellingShingle Mifepristone increases mRNA translation rate, triggers the unfolded protein response, increases autophagic flux, and kills ovarian cancer cells in combination with proteasome or lysosome inhibitors
Zhang, Lei
Autophagic Flux
Bortezomib
Chloroquine
Er Stress
Mifepristone
Mrna Translation
Ovarian Cancer
Ubiquitin Proteasome System
Unfolded Protein Response
title_short Mifepristone increases mRNA translation rate, triggers the unfolded protein response, increases autophagic flux, and kills ovarian cancer cells in combination with proteasome or lysosome inhibitors
title_full Mifepristone increases mRNA translation rate, triggers the unfolded protein response, increases autophagic flux, and kills ovarian cancer cells in combination with proteasome or lysosome inhibitors
title_fullStr Mifepristone increases mRNA translation rate, triggers the unfolded protein response, increases autophagic flux, and kills ovarian cancer cells in combination with proteasome or lysosome inhibitors
title_full_unstemmed Mifepristone increases mRNA translation rate, triggers the unfolded protein response, increases autophagic flux, and kills ovarian cancer cells in combination with proteasome or lysosome inhibitors
title_sort Mifepristone increases mRNA translation rate, triggers the unfolded protein response, increases autophagic flux, and kills ovarian cancer cells in combination with proteasome or lysosome inhibitors
dc.creator.none.fl_str_mv Zhang, Lei
Hapon, María Belén
Goyeneche, Alicia A.
Srinivasan, Rekha
Gamarra Luques, Carlos Diego
Callegari, Eduardo A.
Drappeau, Donis D.
Terpstra, Erin J.
Pan, Bo
Knapp, Jennifer R.
Chien, Jeremy
Wang, Xuejun
Eyster, Kathleen M.
Telleria, Carlos Marcelo
author Zhang, Lei
author_facet Zhang, Lei
Hapon, María Belén
Goyeneche, Alicia A.
Srinivasan, Rekha
Gamarra Luques, Carlos Diego
Callegari, Eduardo A.
Drappeau, Donis D.
Terpstra, Erin J.
Pan, Bo
Knapp, Jennifer R.
Chien, Jeremy
Wang, Xuejun
Eyster, Kathleen M.
Telleria, Carlos Marcelo
author_role author
author2 Hapon, María Belén
Goyeneche, Alicia A.
Srinivasan, Rekha
Gamarra Luques, Carlos Diego
Callegari, Eduardo A.
Drappeau, Donis D.
Terpstra, Erin J.
Pan, Bo
Knapp, Jennifer R.
Chien, Jeremy
Wang, Xuejun
Eyster, Kathleen M.
Telleria, Carlos Marcelo
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Autophagic Flux
Bortezomib
Chloroquine
Er Stress
Mifepristone
Mrna Translation
Ovarian Cancer
Ubiquitin Proteasome System
Unfolded Protein Response
topic Autophagic Flux
Bortezomib
Chloroquine
Er Stress
Mifepristone
Mrna Translation
Ovarian Cancer
Ubiquitin Proteasome System
Unfolded Protein Response
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv The synthetic steroid mifepristone blocks the growth of ovarian cancer cells, yet the mechanism driving such effect is not entirely understood. Unbiased genomic and proteomic screenings using ovarian cancer cell lines of different genetic backgrounds and sensitivities to platinum led to the identification of two key genes upregulated by mifepristone and involved in the unfolded protein response (UPR): the master chaperone of the endoplasmic reticulum (ER), glucose regulated protein (GRP) of 78 kDa, and the CCAAT/enhancer binding protein homologous transcription factor (CHOP). GRP78 and CHOP were upregulated by mifepristone in ovarian cancer cells regardless of p53 status and platinum sensitivity. Further studies revealed that the three UPR-associated pathways, PERK, IRE1α, and ATF6, were activated by mifepristone. Also, the synthetic steroid acutely increased mRNA translation rate, which, if prevented, abrogated the splicing of XBP1 mRNA, a non-translatable readout of IRE1α activation. Moreover, mifepristone increased LC3-II levels due to increased autophagic flux. When the autophagic–lysosomal pathway was inhibited with chloroquine, mifepristone was lethal to the cells. Lastly, doses of proteasome inhibitors that are inadequate to block the activity of the proteasomes, caused cell death when combined with mifepristone; this phenotype was accompanied by accumulation of poly-ubiquitinated proteins denoting proteasome inhibition. The stimulation by mifepristone of ER stress and autophagic flux offers a therapeutic opportunity for utilizing this compound to sensitize ovarian cancer cells to proteasome or lysosome inhibitors.
Fil: Zhang, Lei. University Of South Dakota; Estados Unidos
Fil: Hapon, María Belén. University Of South Dakota; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina
Fil: Goyeneche, Alicia A.. University Of South Dakota; Estados Unidos. McGill University; Canadá
Fil: Srinivasan, Rekha. University Of South Dakota; Estados Unidos
Fil: Gamarra Luques, Carlos Diego. University Of South Dakota; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina
Fil: Callegari, Eduardo A.. University Of South Dakota; Estados Unidos
Fil: Drappeau, Donis D.. University Of South Dakota; Estados Unidos
Fil: Terpstra, Erin J.. University Of South Dakota; Estados Unidos
Fil: Pan, Bo. University Of South Dakota; Estados Unidos
Fil: Knapp, Jennifer R.. University of Kansas; Estados Unidos
Fil: Chien, Jeremy. University of Kansas; Estados Unidos
Fil: Wang, Xuejun. University Of South Dakota; Estados Unidos
Fil: Eyster, Kathleen M.. University Of South Dakota; Estados Unidos
Fil: Telleria, Carlos Marcelo. University Of South Dakota; Estados Unidos. McGill University; Canadá. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
description The synthetic steroid mifepristone blocks the growth of ovarian cancer cells, yet the mechanism driving such effect is not entirely understood. Unbiased genomic and proteomic screenings using ovarian cancer cell lines of different genetic backgrounds and sensitivities to platinum led to the identification of two key genes upregulated by mifepristone and involved in the unfolded protein response (UPR): the master chaperone of the endoplasmic reticulum (ER), glucose regulated protein (GRP) of 78 kDa, and the CCAAT/enhancer binding protein homologous transcription factor (CHOP). GRP78 and CHOP were upregulated by mifepristone in ovarian cancer cells regardless of p53 status and platinum sensitivity. Further studies revealed that the three UPR-associated pathways, PERK, IRE1α, and ATF6, were activated by mifepristone. Also, the synthetic steroid acutely increased mRNA translation rate, which, if prevented, abrogated the splicing of XBP1 mRNA, a non-translatable readout of IRE1α activation. Moreover, mifepristone increased LC3-II levels due to increased autophagic flux. When the autophagic–lysosomal pathway was inhibited with chloroquine, mifepristone was lethal to the cells. Lastly, doses of proteasome inhibitors that are inadequate to block the activity of the proteasomes, caused cell death when combined with mifepristone; this phenotype was accompanied by accumulation of poly-ubiquitinated proteins denoting proteasome inhibition. The stimulation by mifepristone of ER stress and autophagic flux offers a therapeutic opportunity for utilizing this compound to sensitize ovarian cancer cells to proteasome or lysosome inhibitors.
publishDate 2016
dc.date.none.fl_str_mv 2016-08
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/11336/49777
Zhang, Lei; Hapon, María Belén; Goyeneche, Alicia A.; Srinivasan, Rekha; Gamarra Luques, Carlos Diego; et al.; Mifepristone increases mRNA translation rate, triggers the unfolded protein response, increases autophagic flux, and kills ovarian cancer cells in combination with proteasome or lysosome inhibitors; Elsevier; Molecular Oncology; 10; 7; 8-2016; 1099-1117
1574-7891
CONICET Digital
CONICET
url http://hdl.handle.net/11336/49777
identifier_str_mv Zhang, Lei; Hapon, María Belén; Goyeneche, Alicia A.; Srinivasan, Rekha; Gamarra Luques, Carlos Diego; et al.; Mifepristone increases mRNA translation rate, triggers the unfolded protein response, increases autophagic flux, and kills ovarian cancer cells in combination with proteasome or lysosome inhibitors; Elsevier; Molecular Oncology; 10; 7; 8-2016; 1099-1117
1574-7891
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1016/j.molonc.2016.05.001
info:eu-repo/semantics/altIdentifier/url/https://febs.onlinelibrary.wiley.com/doi/abs/10.1016/j.molonc.2016.05.001
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
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
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 13.13397

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