TY - JOUR
T1 - Cisplatin-resistance in oral squamous cell carcinoma
T2 - Regulation by tumor cell-derived extracellular vesicles
AU - Khoo, Xin Hui
AU - Paterson, Ian C.
AU - Goh, Bey Hing
AU - Lee, Wai Leng
N1 - Funding Information:
Funding: This work was supported by Fundamental Research Grant Scheme grants (FRGS/1/2014/SKK01/ MUSM/03/2) from the Ministry of Higher Education Malaysia, Monash University Malaysia Large Strategic Research Grant (LG-2017-02-SCI) and Monash Global Asia in the 21st Century (GA21) research grant (GA-HW-19-L01 & GA-HW-19-S01).
Publisher Copyright:
© 2019 by the authors.
Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.
PY - 2019/8
Y1 - 2019/8
N2 - 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.
AB - 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.
KW - Cisplatin
KW - Drug resistance
KW - Extracellular vesicles
KW - Oral squamous cell carcinoma
KW - Protein profiling
UR - http://www.scopus.com/inward/record.url?scp=85071741596&partnerID=8YFLogxK
U2 - 10.3390/cancers11081166
DO - 10.3390/cancers11081166
M3 - Article
C2 - 31416147
AN - SCOPUS:85071741596
VL - 11
JO - Cancers
JF - Cancers
SN - 2072-6694
IS - 8
M1 - 1166
ER -