Genetic and cellular sensitivity of Caenorhabditis elegans to the chemotherapeutic agent cisplatin

Cisplatin and derivatives are commonly used as chemotherapeutic agents. Although the cytotoxic action of cisplatin on cancer cells is very efficient, clinical oncologists need to deal with two major difficulties, namely the onset of resistance to the drug and the cytotoxic effect in patients. Here,...

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Autores: García-Rodríguez, Francisco J., Martínez-Fernández, Carmen, Brena, David, Kukhtar, Dmytro, Serrat, Xènia, Nadal, Ernest, Boxem, Mike, Honnen, Sebastian, Miranda-Vizuete, Antonio, Villanueva, Alberto, Cerón, Julián
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2018
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/180197
Acceso en línea:http://hdl.handle.net/10261/180197
Access Level:acceso abierto
Palabra clave:Caenorhabditis elegans
RNA-seq
Cisplatin
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spelling Genetic and cellular sensitivity of Caenorhabditis elegans to the chemotherapeutic agent cisplatinGarcía-Rodríguez, Francisco J.Martínez-Fernández, CarmenBrena, DavidKukhtar, DmytroSerrat, XèniaNadal, ErnestBoxem, MikeHonnen, SebastianMiranda-Vizuete, AntonioVillanueva, AlbertoCerón, JuliánCaenorhabditis elegansRNA-seqCisplatinCisplatin and derivatives are commonly used as chemotherapeutic agents. Although the cytotoxic action of cisplatin on cancer cells is very efficient, clinical oncologists need to deal with two major difficulties, namely the onset of resistance to the drug and the cytotoxic effect in patients. Here, we used Caenorhabditis elegans to investigate factors influencing the response to cisplatin in multicellular organisms. In this hermaphroditic model organism, we observed that sperm failure is a major cause of cisplatin-induced infertility. RNA sequencing data indicate that cisplatin triggers a systemic stress response, in which DAF-16/FOXO and SKN-1/NRF2, two conserved transcription factors, are key regulators. We determined that inhibition of the DNA damage-induced apoptotic pathway does not confer cisplatin protection to the animal. However, mutants for the pro-apoptotic BH3-only gene ced-13 are sensitive to cisplatin, suggesting a protective role of the intrinsic apoptotic pathway. Finally, we demonstrated that our system can also be used to identify mutations providing resistance to cisplatin and therefore potential biomarkers of innate cisplatin-refractory patients. We show that mutants for the redox regulator trxr-1, ortholog of the mammalian thioredoxin reductase 1 TRXR1, display cisplatin resistance. By CRISPR/Cas9, we determined that such resistance relies on the presence of the single selenocysteine residue in TRXR-1.This study was supported by grants from the Instituto de Salud Carlos III (ISCIII; PI15/00895 to J.C., PI16/01898 to A.V.), which is co-funded by the European Regional Development Fund/FEDER. The A.V. laboratory was also supported by funding from Ministerio de Economía y Competitividad (BFU2007-67123). M.B. was supported by a Netherlands Organization for Scientific Research (NWO) chemical sciences ECHO grant (711.014.005). E.N. was supported a Sociedad Española de Oncología Médica (SEOM) grant for emerging research groups. F.J.G.-R. was the recipient of a PFIS predoctoral fellowship from ISCIII. A.M.-V. was supported by a grant from Ministerio de Economía y Competitividad (BFU2015-64408-P, co-financed by the European Social Fund) and is a member of the EU-ROS Cost Action of the European Union. J.C., M.B., S.H. and A.M.-V are members of the GENIE EU Cost action. D.B. was recipient of a Consejo Nacional de Ciencia y Tecnología ‘al extranjero’ fellowship (523048).Peer reviewedCompany of BiologistsInstituto de Salud Carlos IIIEuropean CommissionMinisterio de Economía y Competitividad (España)Netherlands Organization for Scientific ResearchSociedad Española de Oncología MédicaConsejo Nacional de Ciencia y Tecnología (México)Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]201920192018info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/180197reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/BFU2015-64408-Phttps://doi.org/10.1242/dmm.033506Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/1801972026-05-22T06:33:51Z
dc.title.none.fl_str_mv Genetic and cellular sensitivity of Caenorhabditis elegans to the chemotherapeutic agent cisplatin
title Genetic and cellular sensitivity of Caenorhabditis elegans to the chemotherapeutic agent cisplatin
spellingShingle Genetic and cellular sensitivity of Caenorhabditis elegans to the chemotherapeutic agent cisplatin
García-Rodríguez, Francisco J.
Caenorhabditis elegans
RNA-seq
Cisplatin
title_short Genetic and cellular sensitivity of Caenorhabditis elegans to the chemotherapeutic agent cisplatin
title_full Genetic and cellular sensitivity of Caenorhabditis elegans to the chemotherapeutic agent cisplatin
title_fullStr Genetic and cellular sensitivity of Caenorhabditis elegans to the chemotherapeutic agent cisplatin
title_full_unstemmed Genetic and cellular sensitivity of Caenorhabditis elegans to the chemotherapeutic agent cisplatin
title_sort Genetic and cellular sensitivity of Caenorhabditis elegans to the chemotherapeutic agent cisplatin
dc.creator.none.fl_str_mv García-Rodríguez, Francisco J.
Martínez-Fernández, Carmen
Brena, David
Kukhtar, Dmytro
Serrat, Xènia
Nadal, Ernest
Boxem, Mike
Honnen, Sebastian
Miranda-Vizuete, Antonio
Villanueva, Alberto
Cerón, Julián
author García-Rodríguez, Francisco J.
author_facet García-Rodríguez, Francisco J.
Martínez-Fernández, Carmen
Brena, David
Kukhtar, Dmytro
Serrat, Xènia
Nadal, Ernest
Boxem, Mike
Honnen, Sebastian
Miranda-Vizuete, Antonio
Villanueva, Alberto
Cerón, Julián
author_role author
author2 Martínez-Fernández, Carmen
Brena, David
Kukhtar, Dmytro
Serrat, Xènia
Nadal, Ernest
Boxem, Mike
Honnen, Sebastian
Miranda-Vizuete, Antonio
Villanueva, Alberto
Cerón, Julián
author2_role author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Instituto de Salud Carlos III
European Commission
Ministerio de Economía y Competitividad (España)
Netherlands Organization for Scientific Research
Sociedad Española de Oncología Médica
Consejo Nacional de Ciencia y Tecnología (México)
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Caenorhabditis elegans
RNA-seq
Cisplatin
topic Caenorhabditis elegans
RNA-seq
Cisplatin
description Cisplatin and derivatives are commonly used as chemotherapeutic agents. Although the cytotoxic action of cisplatin on cancer cells is very efficient, clinical oncologists need to deal with two major difficulties, namely the onset of resistance to the drug and the cytotoxic effect in patients. Here, we used Caenorhabditis elegans to investigate factors influencing the response to cisplatin in multicellular organisms. In this hermaphroditic model organism, we observed that sperm failure is a major cause of cisplatin-induced infertility. RNA sequencing data indicate that cisplatin triggers a systemic stress response, in which DAF-16/FOXO and SKN-1/NRF2, two conserved transcription factors, are key regulators. We determined that inhibition of the DNA damage-induced apoptotic pathway does not confer cisplatin protection to the animal. However, mutants for the pro-apoptotic BH3-only gene ced-13 are sensitive to cisplatin, suggesting a protective role of the intrinsic apoptotic pathway. Finally, we demonstrated that our system can also be used to identify mutations providing resistance to cisplatin and therefore potential biomarkers of innate cisplatin-refractory patients. We show that mutants for the redox regulator trxr-1, ortholog of the mammalian thioredoxin reductase 1 TRXR1, display cisplatin resistance. By CRISPR/Cas9, we determined that such resistance relies on the presence of the single selenocysteine residue in TRXR-1.
publishDate 2018
dc.date.none.fl_str_mv 2018
2019
2019
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/180197
url http://hdl.handle.net/10261/180197
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/BFU2015-64408-P
https://doi.org/10.1242/dmm.033506
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Company of Biologists
publisher.none.fl_str_mv Company of Biologists
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
repository.name.fl_str_mv
repository.mail.fl_str_mv
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