Abstract
Abstract Objectives Temozolomide (TMZ) is an effective drug for glioblastoma multiforme (GBM), but the mechanism underlying TMZ resistance is poorly understood. New evidence has revealed that the release of heat shock proteins (Hsps) derived from extracellular vesicles (EVs) play an important role in cancer progression by modulating tumor microenvironment and cellular cross-talk. This study aims to evaluate the effects of TMZ on the expression of EV-derived and cellular Hsps and cell motility in U87MG human glioblastoma cell line. Methods Glial-EVs were isolated from the culture medium and characterized by SEM and immunoblotting. The effect of TMZ treatments (25, 200 and 750 µM) on cell proliferation (MTT assay), migration (scratch assay), and Hsp60 and Hsp70 levels (immunoblotting) were evaluated. Results TMZ treatments led to an increase in intracellular Hsp70 while decreasing EV-derived Hsp70. Cellular Hsp60 level was elevated at the low dose of TMZ, but it reduced at higher TMZ concentrations. Hsp60 was also decreased in EVs secreted from TMZ-treated cells. Besides, TMZ treatment reduced the proliferation and migration of glioma cells in a dose-dependent manner. Conclusions Our results suggest that TMZ has the potential to target both EV-derived and cellular Hsps for GBM treatment, thus it may reduce cell motility.
Highlights
Glioblastoma multiforme (GBM) is one of the most common primary malignant brain tumors that is highly aggressive and has a poor prognosis
This study aims to evaluate the effects of TMZ on the expression of extracellular vesicles (EVs)-derived and cellular heat shock proteins (Hsps) and cell motility in U87MG human glioblastoma cell line
TMZ treatments led to an increase in intracellular Hsp70 while decreasing EV-derived Hsp70
Summary
Glioblastoma multiforme (GBM) is one of the most common primary malignant brain tumors that is highly aggressive and has a poor prognosis. Acceptable penetration through the blood-brain barrier (BBB), temozolomide (TMZ) is a primarily preferential chemotherapeutic agent, which FDA approved for glioblastoma. TMZ is an alkylating prodrug that breaks the DNA double-strand, leading to cell cycle arrest and resulted in cell death [1, 2]. Once uptake by recipient cells, the tumor-derived EVs can alter the functions of the cells by affecting both surrounding and distal cells to provide a suitable microenvironment for cancer cell proliferation, metastasis, angiogenesis, and development of drug resistance. EVs are widely investigated for their involvement in regulating tumor pathobiology in GBM as well as their use as potential biomarkers [3, 4]
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