Martin, Jack Laurence; (2023) Investigating the Effect of the Ototoxic Chemotherapeutic Cisplatin on Stress Granules In Vitro. Doctoral thesis (Ph.D), UCL (University College London).

Text Jack Martin - PhD Thesis.pdf - Accepted Version Access restricted to UCL open access staff until 1 September 2025. Download (7MB)

Abstract

Cisplatin is a highly effective, but ototoxic, platinum-based chemotherapeutic. The hearing loss that develops in up to 80% of adults and 90% of children (Frisina et al., 2016; van As et al., 2016) undergoing cisplatin chemotherapy is bilateral, sensorineural, progressive and irreversible. The mechanisms underlying cisplatin ototoxicity are not fully understood but there are multiple proteins that have been shown to interact with cisplatin, several of which participate in the formation and regulation of stress granules (SGs), condensations of mRNA and RNA-binding proteins. A role for SGs in protecting against aminoglycoside ototoxicity has been previously identified (Goncalves et al., 2019). Furthermore, recent work has shown that Caprin1, an RNA binding protein and key SG component and regulator is necessary for maintenance of auditory function (Nolan et al., 2022). The effects of cisplatin on SG dynamics and composition in cell lines derived from the cochlea and retinal pigment epithelium was investigated. Cisplatin-induced SGs are significantly diminished in size and quantity compared to arsenite-induced SGs and are persistent after 24 hours recovery. Additionally, cisplatin pre-treated cells were unable to form a typical SG response to subsequent arsenite stress. Cisplatin-induced SGs had significant reductions in the sequestration of eIF4G and proteins RACK1 and DDX3X. Live cell imaging of cisplatin-TR revealed localisation to SGs and retention for at least 24 hours. Taken together, this work has revealed that cisplatin localises to SGs, affecting their dynamics and composition of what could be termed non-canonical SGs. These aberrant/non-canonical SGs could underlie the susceptibility of cochlear cells to cisplatin. They may also provide an explanation for the retention of cisplatin in the cochlea and represent several novel targets for the prevention of cisplatin ototoxicity. These findings may also have wider implications for cisplatin resistant tumours by increasing our understanding of the non-DNA effects of cisplatin treatment.

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