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Dis Model Mech. 2018 Jun 21;11(6). pii: dmm033506. doi: 10.1242/dmm.033506.

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

Author information

1
Modeling human diseases in C. elegans. Genes, Diseases and Therapies Program, Bellvitge Biomedical Research Institute - IDIBELL, L'Hospitalet de Llobregat, 08908 Barcelona, Spain.
2
Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908 Barcelona, Spain.
3
Thoracic Oncology Unit, Department of Medical Oncology, Catalan Institute of Oncology (ICO), L'Hospitalet de Llobregat, 08908 Barcelona, Spain.
4
Division of Developmental Biology, Department of Biology, Faculty of Science, Utrecht University, 3584 CH Utrecht, The Netherlands.
5
Heinrich Heine University Düsseldorf, Medical Faculty, Institute of Toxicology, D-40225 Düsseldorf, Germany.
6
Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, E-41013 Sevilla, Spain.
7
Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908 Barcelona, Spain avillanueva@iconcologia.net jceron@idibell.cat.
8
Modeling human diseases in C. elegans. Genes, Diseases and Therapies Program, Bellvitge Biomedical Research Institute - IDIBELL, L'Hospitalet de Llobregat, 08908 Barcelona, Spain avillanueva@iconcologia.net jceron@idibell.cat.

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.This article has an associated First Person interview with the first author of the paper.

KEYWORDS:

Caenorhabditis elegans; Cisplatin; RNA-seq

Conflict of interest statement

Competing interestsThe authors declare no competing or financial interests.

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