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Methionine deprivation enhances the radiosensitivity of glioma cells and promotes ionizing radiation-induced immunogenic cell death via the endoplasmic reticulum stress signaling pathway
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S. Yang   , H. Qin , X. Jiang , X. Xue , H. Tan , B. Wang , T. Sun , W. Yang |
| State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, Jiangsu, China , detachedy@aliyun.com |
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Abstract: (3 Views) |
Background: Methionine deprivation (MD) affects protein stability, signaling pathway activation and redox status of cancerous cells. In this study, we investigated the effects of MD on the radiosensitivity and radiation-induced immunogenic death of glioma cells and the underlying mechanism. Materials and Methods: Human glioma cells, U251 and T98G, were cultured in DMEM medium with or without methionine under normoxia or hypoxia (1% O2). Cell proliferation, radiosensitivity, and DNA damage repair were detected by EdU assay, colony formation assay, γ-H2AX immunofluorescence staining and single-cell gel electrophoresis, respectively. Cell apoptosis and surface exposure of calreticulin (CRT) were detected via flow cytometry. The expression of autophagy-related proteins microtubule-associated protein 1 light chain 3 (LC3) and P62 and endoplasmic reticulum stress (ERS) pathway-related proteins PKR-like endoplasmic reticulum kinase (PERK) and inositol requiring enzyme 1 alpha (IRE1α) was detected via Western blotting. Results: MD inhibited the proliferation of normoxic or hypoxic glioma cells. MD combined with radiation promoted apoptosis and increased the number of γ-H2AX foci and the percentage of DNA in the tail of the comet. MD enhanced the radiosensitivity of normoxic or hypoxic glioma cells, which was further enhanced when combined with the autophagy inhibitor 3-methyladenine (3-MA). MD enhanced the transformation of LC3 I to LC3 II and decreased the expression of P62. MD also increased radiation-induced CRT exposure, ATP release and PERK and IRE1α phosphorylation. Conclusion: MD enhanced the radiosensitivity of glioma cells by inhibiting DNA repair and promoted ionizing radiation-induced immunogenic cell death through activating the ERS signaling pathway. |
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| Keywords: Methionine, glioma, autophagy, radiosensitivity, immunogenic cell death. |
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Full-Text [PDF 3061 kb]
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Type of Study: Original Research |
Subject:
Radiation Biology
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