Format

Send to

Choose Destination
Dis Model Mech. 2018 May 10. pii: dmm.033506. doi: 10.1242/dmm.033506. [Epub ahead of print]

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, Barcelona, Spain.
2
Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Barcelona, Spain.
3
Thoracic Oncology Unit, Department of Medical Oncology, Catalan Institute of Oncology (ICO), L'Hospitalet de Llobregat, 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, Barcelona, Spain jceron@idibell.cat avillanueva@iconcologia.net.
8
Modeling human diseases in C. elegans. Genes, Diseases and Therapies Program, Bellvitge Biomedical Research Institute - IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain jceron@idibell.cat avillanueva@iconcologia.net.

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: (i) the onset of resistance to the drug, and (ii) the cytotoxic effect in patients. Here we use 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 in cisplatin-induced infertility. RNA-seq 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 demonstrate 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.

KEYWORDS:

C. elegans; Cisplatin; RNA-seq

PMID:
29752286
DOI:
10.1242/dmm.033506
Free full text

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center