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Open AccessArticle

Cisplatin-Resistance in Oral Squamous Cell Carcinoma: Regulation by Tumor Cell-Derived Extracellular Vesicles

1
School of Science, Monash University Malaysia, Subang Jaya 47500, Selangor, Malaysia
2
Department of Oral and Craniofacial Sciences, University Malaya, Kuala Lumpur 50603, Malaysia
3
Biofunctional Molecule Exploratory Research Group (BMEX), School of Pharmacy, Monash University Malaysia, Subang Jaya 47500, Selangor, Malaysia
4
Health and Well-being Cluster, Global Asia in the 21st Century (GA21) Platform, Monash University Malaysia, Subang Jaya 47500, Selangor, Malaysia
*
Author to whom correspondence should be addressed.
Cancers 2019, 11(8), 1166; https://doi.org/10.3390/cancers11081166
Received: 19 June 2019 / Revised: 13 July 2019 / Accepted: 18 July 2019 / Published: 14 August 2019
(This article belongs to the Special Issue Extracellular Vesicles in Cancer Progression and Drug Resistance)
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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. View Full-Text
Keywords: oral squamous cell carcinoma; extracellular vesicles; cisplatin; drug resistance; protein profiling oral squamous cell carcinoma; extracellular vesicles; cisplatin; drug resistance; protein profiling
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Khoo, X.-H.; Paterson, I.C.; Goh, B.-H.; Lee, W.-L. Cisplatin-Resistance in Oral Squamous Cell Carcinoma: Regulation by Tumor Cell-Derived Extracellular Vesicles. Cancers 2019, 11, 1166.

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