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.
Highlights
Oral cancer is ranked the 16th most common form of cancer and accounted for 2% of all newly diagnosed cancer cases in 2018 [1]
There are two main types of drug resistance described in cancers, namely, de novo or intrinsic drug resistance where the cells are inherently insensitive to chemotherapeutic drugs, and acquired or adaptive drug resistance that develops over time after prolonged exposure to chemotherapeutic drugs [4]
H103/cisD2 cells were morphologically different from their parental cells (Figure S1) and demonstrated a similar response to that of the de novo resistant cell line, H314, to cisplatin treatment (Figure 1b)
Summary
Oral cancer is ranked the 16th most common form of cancer and accounted for 2% of all newly diagnosed cancer cases in 2018 [1]. Up to 90% of oral malignancies are diagnosed as oral squamous cell carcinoma (OSCC) [2]. Chemotherapy as an optional combination treatment for OSCC, has been shown to enhance the overall survival of patients with advanced disease. The emergence of drug resistance becomes a major challenge for OSCC patients undergoing chemotherapy [2,3]. There are two main types of drug resistance described in cancers, namely, de novo or intrinsic drug resistance where the cells are inherently insensitive to chemotherapeutic drugs, and acquired or adaptive drug resistance that develops over time after prolonged exposure to chemotherapeutic drugs [4]. Various mechanisms of drug resistance have been identified [5] and recently, extracellular vesicles have been identified as a key regulator of drug resistance in many cancer types
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