EIF2 kinases mediate β-lapachone toxicity in yeast and human cancer cells

Autores
Menacho Márquez, Mauricio Ariel; Rodríguez Hernández, Carlos J.; Villarong, M. Ángeles; Pérez Valle, Jorge; Gadea, José; Belandia, Borja; Murguía, José R.
Año de publicación
2015
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
β-lapachone (β-lap) is a novel anticancer agent that selectively induces cell death in human cancer cells, by activation of the NQO1 NAD(P)H dehydrogenase and radical oxygen species (ROS) generation. We characterized the gene expression profile of budding yeast cells treated with β-lap using cDNA microarrays. Genes involved in tolerance to oxidative stress were differentially expressed in bβ-lap treated cells. β-lap treatment generated reactive oxygen species (ROS), which were efficiently blocked by dicoumarol, an inhibitor of NADH dehydrogenases. A yeast mutant in the mitocondrial NADH dehydrogenase Nde2p was found to be resistant to β-lap treatment, despite inducing ROS production in a WT manner. Most interestingly, DNA damage responses triggered by β-lap were abolished in the nde2D mutant. Amino acid biosynthesis genes were also induced in β-lap treated cells, suggesting that β-lap exposure somehow triggered the General Control of Nutrients (GCN) pathway. Accordingly, β-lap treatment increased phosphorylation of eIF2α subunit in a manner dependent on the Gcn2p kinase. eIF2α phosphorylation required Gcn1p, Gcn20p and Nde2p. Gcn2p was also required for cell survival upon exposure to β-lap and to elicit checkpoint responses. Remarkably, β-lap treatment increased phosphorylation of eIF2α in breast tumor cells, in a manner dependent on the Nde2p ortholog AIF, and the eIF2 kinase PERK. These findings uncover a new target pathway of β-lap in yeast and human cells and highlight a previously unknown functional connection between Nde2p, Gcn2p and DNA damage responses.
Fil: Menacho Márquez, Mauricio Ariel. Universidad Nacional de Rosario. Facultad de Ciencias Medicas. Instituto de Genetica Experimental; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; Argentina
Fil: Rodríguez Hernández, Carlos J.. Hospital Sant Joan de Déu; España
Fil: Villarong, M. Ángeles. Instituto Universitario de Oncología del Principado de Asturias; España
Fil: Pérez Valle, Jorge. Instituto de Biología Molecular de Barcelona; España
Fil: Gadea, José. Instituto de Biología Molecular y Celular de Plantas; España
Fil: Belandia, Borja. Consejo Superior de Investigaciones Científicas; España. Universidad Autónoma de Madrid; España
Fil: Murguía, José R.. Universidad Politécnica de Valencia; España
Materia
ANTITUMORAL DRUG
DNA DAMAGE
INTEGRATED STRESS RESPONSE
REACTIVE OXYGEN SPECIES
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:11336/37916
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/37916
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling EIF2 kinases mediate β-lapachone toxicity in yeast and human cancer cellsMenacho Márquez, Mauricio ArielRodríguez Hernández, Carlos J.Villarong, M. ÁngelesPérez Valle, JorgeGadea, JoséBelandia, BorjaMurguía, José R.ANTITUMORAL DRUGDNA DAMAGEINTEGRATED STRESS RESPONSEREACTIVE OXYGEN SPECIEShttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1β-lapachone (β-lap) is a novel anticancer agent that selectively induces cell death in human cancer cells, by activation of the NQO1 NAD(P)H dehydrogenase and radical oxygen species (ROS) generation. We characterized the gene expression profile of budding yeast cells treated with β-lap using cDNA microarrays. Genes involved in tolerance to oxidative stress were differentially expressed in bβ-lap treated cells. β-lap treatment generated reactive oxygen species (ROS), which were efficiently blocked by dicoumarol, an inhibitor of NADH dehydrogenases. A yeast mutant in the mitocondrial NADH dehydrogenase Nde2p was found to be resistant to β-lap treatment, despite inducing ROS production in a WT manner. Most interestingly, DNA damage responses triggered by β-lap were abolished in the nde2D mutant. Amino acid biosynthesis genes were also induced in β-lap treated cells, suggesting that β-lap exposure somehow triggered the General Control of Nutrients (GCN) pathway. Accordingly, β-lap treatment increased phosphorylation of eIF2α subunit in a manner dependent on the Gcn2p kinase. eIF2α phosphorylation required Gcn1p, Gcn20p and Nde2p. Gcn2p was also required for cell survival upon exposure to β-lap and to elicit checkpoint responses. Remarkably, β-lap treatment increased phosphorylation of eIF2α in breast tumor cells, in a manner dependent on the Nde2p ortholog AIF, and the eIF2 kinase PERK. These findings uncover a new target pathway of β-lap in yeast and human cells and highlight a previously unknown functional connection between Nde2p, Gcn2p and DNA damage responses.Fil: Menacho Márquez, Mauricio Ariel. Universidad Nacional de Rosario. Facultad de Ciencias Medicas. Instituto de Genetica Experimental; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; ArgentinaFil: Rodríguez Hernández, Carlos J.. Hospital Sant Joan de Déu; EspañaFil: Villarong, M. Ángeles. Instituto Universitario de Oncología del Principado de Asturias; EspañaFil: Pérez Valle, Jorge. Instituto de Biología Molecular de Barcelona; EspañaFil: Gadea, José. Instituto de Biología Molecular y Celular de Plantas; EspañaFil: Belandia, Borja. Consejo Superior de Investigaciones Científicas; España. Universidad Autónoma de Madrid; EspañaFil: Murguía, José R.. Universidad Politécnica de Valencia; EspañaLandes Bioscience2015-02info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/37916Menacho Márquez, Mauricio Ariel; Rodríguez Hernández, Carlos J.; Villarong, M. Ángeles; Pérez Valle, Jorge; Gadea, José; et al.; EIF2 kinases mediate β-lapachone toxicity in yeast and human cancer cells; Landes Bioscience; Cell Cycle; 14; 4; 2-2015; 630-6401538-4101CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.4161/15384101.2014.994904info:eu-repo/semantics/altIdentifier/url/https://www.tandfonline.com/doi/full/10.4161/15384101.2014.994904info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:50:40Zoai:ri.conicet.gov.ar:11336/37916instacron: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 09:50:40.977CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv EIF2 kinases mediate β-lapachone toxicity in yeast and human cancer cells
title EIF2 kinases mediate β-lapachone toxicity in yeast and human cancer cells
spellingShingle EIF2 kinases mediate β-lapachone toxicity in yeast and human cancer cells
Menacho Márquez, Mauricio Ariel
ANTITUMORAL DRUG
DNA DAMAGE
INTEGRATED STRESS RESPONSE
REACTIVE OXYGEN SPECIES
title_short EIF2 kinases mediate β-lapachone toxicity in yeast and human cancer cells
title_full EIF2 kinases mediate β-lapachone toxicity in yeast and human cancer cells
title_fullStr EIF2 kinases mediate β-lapachone toxicity in yeast and human cancer cells
title_full_unstemmed EIF2 kinases mediate β-lapachone toxicity in yeast and human cancer cells
title_sort EIF2 kinases mediate β-lapachone toxicity in yeast and human cancer cells
dc.creator.none.fl_str_mv Menacho Márquez, Mauricio Ariel
Rodríguez Hernández, Carlos J.
Villarong, M. Ángeles
Pérez Valle, Jorge
Gadea, José
Belandia, Borja
Murguía, José R.
author Menacho Márquez, Mauricio Ariel
author_facet Menacho Márquez, Mauricio Ariel
Rodríguez Hernández, Carlos J.
Villarong, M. Ángeles
Pérez Valle, Jorge
Gadea, José
Belandia, Borja
Murguía, José R.
author_role author
author2 Rodríguez Hernández, Carlos J.
Villarong, M. Ángeles
Pérez Valle, Jorge
Gadea, José
Belandia, Borja
Murguía, José R.
author2_role author
author
author
author
author
author
dc.subject.none.fl_str_mv ANTITUMORAL DRUG
DNA DAMAGE
INTEGRATED STRESS RESPONSE
REACTIVE OXYGEN SPECIES
topic ANTITUMORAL DRUG
DNA DAMAGE
INTEGRATED STRESS RESPONSE
REACTIVE OXYGEN SPECIES
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv β-lapachone (β-lap) is a novel anticancer agent that selectively induces cell death in human cancer cells, by activation of the NQO1 NAD(P)H dehydrogenase and radical oxygen species (ROS) generation. We characterized the gene expression profile of budding yeast cells treated with β-lap using cDNA microarrays. Genes involved in tolerance to oxidative stress were differentially expressed in bβ-lap treated cells. β-lap treatment generated reactive oxygen species (ROS), which were efficiently blocked by dicoumarol, an inhibitor of NADH dehydrogenases. A yeast mutant in the mitocondrial NADH dehydrogenase Nde2p was found to be resistant to β-lap treatment, despite inducing ROS production in a WT manner. Most interestingly, DNA damage responses triggered by β-lap were abolished in the nde2D mutant. Amino acid biosynthesis genes were also induced in β-lap treated cells, suggesting that β-lap exposure somehow triggered the General Control of Nutrients (GCN) pathway. Accordingly, β-lap treatment increased phosphorylation of eIF2α subunit in a manner dependent on the Gcn2p kinase. eIF2α phosphorylation required Gcn1p, Gcn20p and Nde2p. Gcn2p was also required for cell survival upon exposure to β-lap and to elicit checkpoint responses. Remarkably, β-lap treatment increased phosphorylation of eIF2α in breast tumor cells, in a manner dependent on the Nde2p ortholog AIF, and the eIF2 kinase PERK. These findings uncover a new target pathway of β-lap in yeast and human cells and highlight a previously unknown functional connection between Nde2p, Gcn2p and DNA damage responses.
Fil: Menacho Márquez, Mauricio Ariel. Universidad Nacional de Rosario. Facultad de Ciencias Medicas. Instituto de Genetica Experimental; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; Argentina
Fil: Rodríguez Hernández, Carlos J.. Hospital Sant Joan de Déu; España
Fil: Villarong, M. Ángeles. Instituto Universitario de Oncología del Principado de Asturias; España
Fil: Pérez Valle, Jorge. Instituto de Biología Molecular de Barcelona; España
Fil: Gadea, José. Instituto de Biología Molecular y Celular de Plantas; España
Fil: Belandia, Borja. Consejo Superior de Investigaciones Científicas; España. Universidad Autónoma de Madrid; España
Fil: Murguía, José R.. Universidad Politécnica de Valencia; España
description β-lapachone (β-lap) is a novel anticancer agent that selectively induces cell death in human cancer cells, by activation of the NQO1 NAD(P)H dehydrogenase and radical oxygen species (ROS) generation. We characterized the gene expression profile of budding yeast cells treated with β-lap using cDNA microarrays. Genes involved in tolerance to oxidative stress were differentially expressed in bβ-lap treated cells. β-lap treatment generated reactive oxygen species (ROS), which were efficiently blocked by dicoumarol, an inhibitor of NADH dehydrogenases. A yeast mutant in the mitocondrial NADH dehydrogenase Nde2p was found to be resistant to β-lap treatment, despite inducing ROS production in a WT manner. Most interestingly, DNA damage responses triggered by β-lap were abolished in the nde2D mutant. Amino acid biosynthesis genes were also induced in β-lap treated cells, suggesting that β-lap exposure somehow triggered the General Control of Nutrients (GCN) pathway. Accordingly, β-lap treatment increased phosphorylation of eIF2α subunit in a manner dependent on the Gcn2p kinase. eIF2α phosphorylation required Gcn1p, Gcn20p and Nde2p. Gcn2p was also required for cell survival upon exposure to β-lap and to elicit checkpoint responses. Remarkably, β-lap treatment increased phosphorylation of eIF2α in breast tumor cells, in a manner dependent on the Nde2p ortholog AIF, and the eIF2 kinase PERK. These findings uncover a new target pathway of β-lap in yeast and human cells and highlight a previously unknown functional connection between Nde2p, Gcn2p and DNA damage responses.
publishDate 2015
dc.date.none.fl_str_mv 2015-02
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/11336/37916
Menacho Márquez, Mauricio Ariel; Rodríguez Hernández, Carlos J.; Villarong, M. Ángeles; Pérez Valle, Jorge; Gadea, José; et al.; EIF2 kinases mediate β-lapachone toxicity in yeast and human cancer cells; Landes Bioscience; Cell Cycle; 14; 4; 2-2015; 630-640
1538-4101
CONICET Digital
CONICET
url http://hdl.handle.net/11336/37916
identifier_str_mv Menacho Márquez, Mauricio Ariel; Rodríguez Hernández, Carlos J.; Villarong, M. Ángeles; Pérez Valle, Jorge; Gadea, José; et al.; EIF2 kinases mediate β-lapachone toxicity in yeast and human cancer cells; Landes Bioscience; Cell Cycle; 14; 4; 2-2015; 630-640
1538-4101
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.4161/15384101.2014.994904
info:eu-repo/semantics/altIdentifier/url/https://www.tandfonline.com/doi/full/10.4161/15384101.2014.994904
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 Landes Bioscience
publisher.none.fl_str_mv Landes Bioscience
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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