Abstract
ABSTRACTCisplatin 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.
Highlights
The US Food and Drug Administration approved the use of cisplatin [CDDP, cis-diammine-dichloroplatinum(II)] as a chemotherapeutic agent in 1978
A reliable assay to study the effect of cisplatin in C. elegans In C. elegans nematodes, cisplatin produces a wide variety of phenotypes depending on the concentration, length of treatment and developmental stage of the treated animals (Tables S1 and S2)
The BH3-only protein CED-13 protects against cisplatin We demonstrate, for the first time, that cisplatin leads to the formation of DNA adducts in C. elegans (Fig. 4A) and induces the expression of two apoptosis-related genes, egl-1 and ced-13, which encode BH3-only proteins, which are a subset of the Bcl-2 familiy that contain only a BH3 domain and promote apoptosis. egl-1 and ced-13 are transcriptionally induced upon DNA damage, and this induction is CEP-1/P53 dependent (Greiss et al, 2008)
Summary
The US Food and Drug Administration approved the use of cisplatin [CDDP, cis-diammine-dichloroplatinum(II)] as a chemotherapeutic agent in 1978. Cisplatin and other platinum-based derivatives have been used successfully in cancer treatment. To illustrate their impact in the clinic, it has been estimated that approximately half of all patients undergoing chemotherapeutic treatment receive a platinum drug (Galanski, 2006). Cisplatin exerts activity against a wide spectrum of solid neoplasms, including testicular, bladder, ovarian, head and neck, gastric and lung cancers (Dasari and Bernard Tchounwou, 2014). Testicular cancer was previously fatal, but treatment with cisplatin provided a cure for 80% of the patients (Gonzalez-Exposito et al, 2016). There are patients intrinsically resistant to cisplatin-based therapies, and an important fraction of tumors eventually develop chemoresistance (Amable, 2016)
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