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

 

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dc.creator García-Rodríguez, Francisco Javier es
dc.creator Martínez-Fernández, Carmen es
dc.creator Brena, David es
dc.creator Kukhtar, Dmytro es
dc.creator Serrat, Xènia es
dc.creator Nadal, Ernest es
dc.creator Boxem, Mike es
dc.creator Honnen, Sebastian es
dc.creator Miranda Vizuete, Antonio es
dc.creator Villanueva, Alberto es
dc.creator Cerón, Julián es
dc.date.accessioned 2018-08-22T11:38:02Z
dc.date.available 2018-08-22T11:38:02Z
dc.date.issued 2018-06-21
dc.identifier.citation García-Rodríguez, F.J., Martínez-Fernández, C., Brena, D., Kukhtar, D., Serrat, X., Nadal, E.,...,Cerón, J. (2018). Genetic and cellular sensitivity of Caenorhabditis elegans to the chemotherapeutic agent cisplatin. Disease Models and Mechanisms, 11 (6), 033506-1-033506-11.
dc.identifier.issn 1754-8403 es
dc.identifier.issn 1754-8411 es
dc.identifier.uri https://hdl.handle.net/11441/78208
dc.description.abstract 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. es
dc.description.sponsorship Instituto de Salud Carlos III PI15/00895 PI16/01898 es
dc.description.sponsorship European Regional Development Fund/FEDER es
dc.description.sponsorship Netherlands Organization for Scientific Research 711.014.005 es
dc.description.sponsorship Sociedad Española de Oncología Médica es
dc.description.sponsorship Ministerio de Economía y Competitividad BFU2007-67123 BFU2015-64408-P es
dc.description.sponsorship European Social Fund BFU2015-64408-P es
dc.format application/pdf es
dc.language.iso eng es
dc.publisher Company of Biologists Limited es
dc.relation.ispartof Disease Models and Mechanisms, 11 (6), 033506-1-033506-11.
dc.rights Attribution-NonCommercial-NoDerivatives 4.0 Internacional *
dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/ *
dc.subject Caenorhabditis elegans es
dc.subject RNA-seq es
dc.subject Cisplatin es
dc.title Genetic and cellular sensitivity of Caenorhabditis elegans to the chemotherapeutic agent cisplatin es
dc.type info:eu-repo/semantics/article es
dc.type.version info:eu-repo/semantics/publishedVersion es
dc.rights.accessrights info:eu-repo/semantics/openAccess es
dc.contributor.affiliation Instituto de Biomedicina de Sevilla (IBIS) es
dc.relation.projectID PI15/00895 es
dc.relation.projectID PI16/01898 es
dc.relation.projectID 711.014.005 es
dc.relation.projectID BFU2007-67123 es
dc.relation.projectID BFU2015-64408-P es
dc.relation.publisherversion http://doi.org/10.1242/dmm.033506 es
dc.identifier.doi 10.1242/dmm.033506 es
idus.format.extent 11 p. es
dc.journaltitle Disease Models and Mechanisms es
dc.publication.volumen 11 es
dc.publication.issue 6 es
dc.publication.initialPage 033506-1 es
dc.publication.endPage 033506-11 es
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