Cisplatin-resistance in oral squamous cell carcinoma: Regulation by tumor cell-derived extracellular vesicles

Xin Hui Khoo, Ian C. Paterson, Bey Hing Goh, Wai Leng Lee

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    15 Citations (Scopus)

    Abstract

    Drug resistance remains a severe problem in most chemotherapy regimes. Recently, it has been suggested that cancer cell-derived extracellular vesicles (EVs) could mediate drug resistance. In this study, the role of EVs in mediating the response of oral squamous cell carcinoma (OSCC) cells to cisplatin was investigated. We isolated and characterized EVs from OSCC cell lines showing differential sensitivities to cisplatin. Increased EV production was observed in both de novo (H314) and adaptive (H103/cisD2) resistant lines compared to sensitive H103 cells. The protein profiles of these EVs were then analyzed. Differences in the proteome of EVs secreted by H103 and H103/cisD2 indicated that adaptation to cisplatin treatment caused significant changes in the secreted nanovesicles. Intriguingly, both resistant H103/cisD2 and H314 cells shared a highly similar EV protein profile including downregulation of the metal ion transporter, ATP1B3, in the EVs implicating altered drug delivery. ICP-MS analysis revealed that less cisplatin accumulated in the resistant cells, but higher levels were detected in their EVs. Therefore, we inhibited EV secretion from the cells using a proton pump inhibitor and observed an increased drug sensitivity in cisplatin-resistant H314 cells. This finding suggests that control of EV secretion could be a potential strategy to enhance the efficacy of cancer treatment.

    Original languageEnglish
    Article number1166
    Number of pages17
    JournalCancers
    Volume11
    Issue number8
    DOIs
    Publication statusPublished - Aug 2019

    Keywords

    • Cisplatin
    • Drug resistance
    • Extracellular vesicles
    • Oral squamous cell carcinoma
    • Protein profiling

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