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

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.

Overcoming Limitations of Cisplatin Therapy by Additional Treatment With the HSP90 Inhibitor Onalespib

“…The human ovarian cancer cell line SKOV3 (doubling time 24 h) obtained from American Type Culture Collection (ATCC, Manassas, VA, United States) was cultured in RPMI 1640 medium (Biochrom GmbH, Berlin, Germany) supplemented with 10% fetal bovine serum (FBS) (Sigma Aldrich, St. Louis, United States), 2 mM L-glutamine (Biochrom GmbH) and antibiotics (100 IU penicillin and 100 μg/ml streptomycin, Biochrom GmbH) ( 24 ). The human head and neck squamous cell carcinoma cell line H314 (doubling time 34 h) was obtained from The European Collection of Authenticated Cell Cultures (ECACC, Salisbury, United Kingdom) and was cultured in Dulbecco’s Modified Eagle Medium/Ham’s F-12 medium (1:1, Biochrom GmbH) with the previously described supplements ( 25 ). The human ovarian cancer cell lines A2780 and the cisplatin resistant clone A2780CIS (doubling times of 18 h) were obtained from The European Collection of Authenticated Cell Cultures and cultured in RPMI 1640 medium with the previously described supplements ( 26 ).…”

Mouse Tumor-Bearing Models as Preclinical Study Platforms for Oral Squamous Cell Carcinoma

“…Although cancer treatments have developed rapidly, the 5-year survival rate for OSCC is still only remained at 50% over the last few decades (3)(4)(5). Given the high incidence and poor prognosis of OSCC, an increasing number of researchers are conducting in-depth investigations into the pathogenesis and potential therapeutic targets of OSCC (6)(7)(8)(9)(10).…”

Streptomyces sp. MUM256: A Source for Apoptosis Inducing and Cell Cycle-Arresting Bioactive Compounds against Colon Cancer Cells

“…However, chemotherapy suffers from significant limitations including insufficient selectivity for tumor cells, leading to many adverse side effects [4,5]. Although targeted therapies have been regarded as the most successful treatments of cancer for the past few decades, genetic mutations greatly affect the efficacy of various targeted drug therapies and leading to mutation-driven resistance of targeted therapy [6,7,8]. Thus, there is an urgent need to search for alternative chemotherapeutic/chemoprevention agents which may overcome the limitations of chemotherapy, and natural products are an excellent resource to explore [9].…”