Abstract

The presence of glioma stem cells (GSCs), which are enriched in neurospheres, may be connected to the radioresistance of glioblastoma (GBM) due to their enhanced antioxidant defense and elevated DNA repair capacity. The aim was to evaluate the responses to different radiation qualities and to reduce radioresistance of U87MG cells, a GBM cell line. U87MG cells were cultured in a 3D model and irradiated with low (24 mGy/h) and high (0.39 Gy/min) dose rates of low LET gamma and high LET carbon ions (1-2 Gy/min). Thereafter, expression of proteins related to oxidative stress response, extracellular 8-oxo-dG, and neurospheres were determined. LD50 for carbon ions was significantly lower compared to LD50 of high and low dose rate gamma radiation. A significantly higher level of 8-oxo-dG was detected in the media of cells exposed to a low dose rate as compared to a high dose rate of gamma or carbon ions. A downregulation of oxidative stress proteins was also observed (NRF2, hMTH1, and SOD1). The NRF2 gene was knocked down by CRISPR/Cas9 in neurosphere cells, resulting in less self-renewal, more differentiated cells, and less proliferation capacity after irradiation with low and high dose rate gamma rays. Overall, U87MG glioma neurospheres presented differential responses to distinct radiation qualities and NRF2 plays an important role in cellular sensitivity to radiation.

Highlights

  • Glioblastoma (GBM) is the most common type of malignant brain tumor in adults reaching 3.6 cases per 100,000 persons per year in Europe [1]

  • The results showed a trend of downregulation of GSS, APE1, SOD1, SOD2, and NRF2 in almost all cell lines when compared to neurospheres (Figures 5(a) and 5(b))

  • We showed that the efficiency of neurosphere formation analyzed for U87MG cells was 27% and cells within the neurospheres expressed 34% higher MUSASHI-1 marker compared with differentiated cells, as analyzed by Western Blot

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Summary

Introduction

Glioblastoma (GBM) is the most common type of malignant brain tumor in adults reaching 3.6 cases per 100,000 persons per year in Europe [1]. Survival of GBM patients is around 12–15 months after diagnosis, even after surgical resection, chemo-, and radiotherapy [2]. The poor prognosis for GBM patients is due to the GBM resistance to chemotherapy and ionizing radiation [4], which may be linked to cancer stem cells (CSCs) in the tumor mass [5,6,7]. The resistance ability of CSCs appears to be associated with their slow-cycling phenotype, and/or expression of efflux transporters, antiapoptotic proteins, altered profile of cell surface markers, effective DNA damage response and repair mechanisms, or the presence of elevated free radical scavengers (reviewed in [8]).

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