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 Garatachea, Alberto, Cerón Madrigal, Julián
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2018
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/172420
Acceso en línea:https://hdl.handle.net/2445/172420
Access Level:acceso abierto
Palabra clave:Nematodes
Quimioteràpia
Chemotherapy
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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 Garatachea, AlbertoCerón Madrigal, JuliánNematodesQuimioteràpiaNematodesChemotherapyCisplatin 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 proapoptotic 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 article has an associated First Person interview with the first author of the paper.Company of Biologists Ltd.2020202020182020info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion11 p.application/pdfhttps://hdl.handle.net/2445/172420Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a: https://doi.org/10.1242/dmm.033506Disease Models & Mechanisms, 2018, vol. 11, num. 6https://doi.org/10.1242/dmm.033506cc by (c) Company of Biologists Ltd., 2018http://creativecommons.org/licenses/by/3.0/es/info:eu-repo/semantics/openAccessoai:recercat.cat:2445/1724202026-05-29T05:05:01Z
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.
Nematodes
Quimioteràpia
Nematodes
Chemotherapy
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 Garatachea, Alberto
Cerón Madrigal, 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 Garatachea, Alberto
Cerón Madrigal, Julián
author_role author
author2 Martínez Fernández, Carmen
Brena, David
Kukhtar, Dmytro
Serrat, Xènia
Nadal, Ernest
Boxem, Mike
Honnen, Sebastian
Miranda Vizuete, Antonio
Villanueva Garatachea, Alberto
Cerón Madrigal, Julián
author2_role author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Nematodes
Quimioteràpia
Nematodes
Chemotherapy
topic Nematodes
Quimioteràpia
Nematodes
Chemotherapy
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 proapoptotic 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 article has an associated First Person interview with the first author of the paper.
publishDate 2018
dc.date.none.fl_str_mv 2018
2020
2020
2020
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/172420
url https://hdl.handle.net/2445/172420
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1242/dmm.033506
Disease Models & Mechanisms, 2018, vol. 11, num. 6
https://doi.org/10.1242/dmm.033506
dc.rights.none.fl_str_mv cc by (c) Company of Biologists Ltd., 2018
http://creativecommons.org/licenses/by/3.0/es/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc by (c) Company of Biologists Ltd., 2018
http://creativecommons.org/licenses/by/3.0/es/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 11 p.
application/pdf
dc.publisher.none.fl_str_mv Company of Biologists Ltd.
publisher.none.fl_str_mv Company of Biologists Ltd.
dc.source.none.fl_str_mv Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,811543

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