Abstract
BackgroundIonizing radiation (IR) therapy is the standard first-line treatment for newly diagnosed patients with glioblastoma (GBM), the most common and malignant primary brain tumor. However, the effects of IR are limited due to the aberrant radioresistance of GBM.MethodsTranscriptome analysis was performed using RNA-seq in radioresistant patient-derived glioma stem-like cells (GSCs). Survival of glioma patient and mice bearing-brain tumors was analyzed by Kaplan–Meier survival analysis. Lipid droplet and γ-H2AX foci-positive cells were evaluated using immunofluorescence staining.ResultsLipolytic inhibitor G0/G1 switch gene 2 (G0S2) is upregulated in radioresistant GSCs and elevated in clinical GBM. GBM patients with high G0S2 expression had significantly shorter overall survival compared with those with low expression of G0S2. Using genetic approaches targeting G0S2 in glioma cells and GSCs, we found that knockdown of G0S2 promoted lipid droplet turnover, inhibited GSC radioresistance, and extended survival of xenograft tumor mice with or without IR. In contrast, overexpression of G0S2 promoted glioma cell radiation resistance. Mechanistically, high expression of G0S2 reduced lipid droplet turnover and thereby attenuated E3 ligase RNF168-mediated 53BP1 ubiquitination through activated the mechanistic target of rapamycin (mTOR)-ribosomal S6 kinase (S6K) signaling and increased 53BP1 protein stability in response to IR, leading to enhanced DNA repair and glioma radioresistance.ConclusionsOur findings uncover a new function for lipolytic inhibitor G0S2 as an important regulator for GSC radioresistance, suggesting G0S2 as a potential therapeutic target for treating gliomas.
Highlights
Glioblastoma (GBM), a WHO grade IV brain tumor is the most common and malignant primary cancer of the central nervous system with a grim median survival of 14.6 months upon diagnosis [1]
G0/G1 switch gene 2 (G0S2) is upregulated in radioresistant glioma stem cells To identify novel mediators of radiation resistance in GBM, we treated a patient-derived glioma stem cell (GSC) line (GSC 1123-C) with repeated fractionated radiation to establish a radioresistant GSC line (GSC 1123-R)
Clonogenic assays showed that the surviving fraction of cells receiving single 4- or 6-Gy Ionizing radiation (IR) was significantly higher for GSC 1123-R cells than for GSC 1123-C cells (Additional file 1: Figure S1D and S1E)
Summary
Glioblastoma (GBM), a WHO grade IV brain tumor is the most common and malignant primary cancer of the central nervous system with a grim median survival of 14.6 months upon diagnosis [1]. Radiotherapy is the standard first line treatment for newly diagnosed patients with gliomas, but its effectiveness is limited given. G0S2 has been shown to play various important roles in cellular functions such as cell proliferation [13], apoptosis [10], and oxidative phosphorylation [9] in humans and mice. Wang et al Journal of Experimental & Clinical Cancer Research (2019) 38:147 identified as a signature of GBM and inversely correlated with GBM patient survival [14]. Ionizing radiation (IR) therapy is the standard first-line treatment for newly diagnosed patients with glioblastoma (GBM), the most common and malignant primary brain tumor. The effects of IR are limited due to the aberrant radioresistance of GBM
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