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Garcia-RodriguezFJ.pdf (4.46 MB)

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Data de publicació

2018-06-01

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cc by (c) Company of Biologists Ltd., 2018
Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/172420

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

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Recurs relacionat

https://doi.org/10.1242/dmm.033506

Resum

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.

Matèries

Nematodes, Quimioteràpia

Matèries (anglès)

Nematodes, Chemotherapy

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Col·leccions

Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

Citació

GARCÍA RODRÍGUEZ, Francisco J., et al. Genetic and cellular sensitivity of Caenorhabditis elegans to the chemotherapeutic agent cisplatin. Disease Models & Mechanisms. 2018. Vol. 11, num. 6. [consulted: 4 of August of 2026]. Available at: https://hdl.handle.net/2445/172420

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