RT Journal Article SR Electronic T1 Genetic and cellular sensitivity of Caenorhabditis elegans to the chemotherapeutic agent cisplatin JF bioRxiv FD Cold Spring Harbor Laboratory SP 233023 DO 10.1101/233023 A1 García-Rodríguez, Francisco Javier A1 Martínez-Fernández, Carmen A1 Brena, David A1 Nadal, Ernest A1 Boxem, Mike A1 Honnen, Sebastian A1 Miranda-Vizuete, Antonio A1 Villanueva, Alberto A1 Cerón, Julián YR 2017 UL http://biorxiv.org/content/early/2017/12/12/233023.abstract AB 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 and that such resistance relies on a single selenocysteine residue.