|
Methionine deprivation enhances the radiosensitivity of glioma cells and promotes ionizing radiation-induced immunogenic cell death via the endoplasmic reticulum stress signaling pathway
|
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 |
|
|
Abstract: (511 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. |
|
| Keywords: Methionine, glioma, autophagy, radiosensitivity, immunogenic cell death. |
|
|
Full-Text [PDF 3061 kb]
(200 Downloads)
|
|
Type of Study: Original Research |
Subject:
Radiation Biology
|
|
|
|
|
|
|
| References |
1. Ruan J, Qin Z, Chen P, Chen Y, Fang J, Tang H (2025) Paeonol combined with radiotherapy inhibits the growth of human glioblastoma by inhibiting the two angiogenesis pathways of VEGF/VEGFR and ANG/Tie-2 in-vitro. Int J Radiat Res, 23(3): 643-650. [ DOI:10.61882/ijrr.23.3.19] 2. Zhu H, Luo J (2023) Postoperative intensity-modulated radiotherapy and chemotherapy in patients with high-grade glioma: analysis of efficacy and prognostic factors. Int J Radiat Res, 21(1): 139-145. 3. Singh S, Dey D, Barik D, Mohapatra I, Kim S, Sharma M, et al. (2025) Glioblastoma at the crossroads: current understanding and future therapeutic horizons. Signal Transduct Target Ther, 10(1): 213. [ DOI:10.1038/s41392-025-02299-4] 4. Nomura M, Spitzer A, Johnson KC, Garofano L, Nehar-Belaid D, Galili Darnell N, et al. (2025) The multilayered transcriptional architecture of glioblastoma ecosystems. Nat Genet, 57(5): 1155-1167. [ DOI:10.1038/s41588-025-02167-5] 5. Qian J and Rankin EB (2019) Hypoxia-induced phenotypes that mediate tumor heterogeneity. Adv Exp Med Biol, 1136: 43-55. [ DOI:10.1007/978-3-030-12734-3_3] 6. Sanderson SM, Gao X, Dai Z, Locasale JW (2019) Methionine metabolism in health and cancer: a nexus of diet and precision medicine. Nature Reviews Cancer, 19: 625-637. [ DOI:10.1038/s41568-019-0187-8] 7. Liu H, Zhang W, Wang K, Wang X, Yin F, Li C, et al. (2015) Methionine and cystine double deprivation stress suppresses glioma proliferation via inducing ROS/autophagy. Toxicol lett, 232: 349-355. [ DOI:10.1016/j.toxlet.2014.11.011] 8. Gao X, Sanderson SM, Dai Z, Reid MA, Cooper DE, Lu M, et al. (2019) Dietary methionine links nutrition and metabolism to the efficacy of cancer therapies. Nature, 572: 397-401. [ DOI:10.1038/s41586-019-1437-3] 9. Cao W, Li J, Yang K, Cao D (2021) An overview of autophagy: Mechanism, regulation and research progress. Bull cancer, 108: 304-322. [ DOI:10.1016/j.bulcan.2020.11.004] 10. Liu H, Xiao Y, Dai C, Chen K, Xu X, Cai J, et al. (2025) Research Advances of the Autophagy-Regulated Radiosensitivity. Cell Prolif, 58(10): e70056. [ DOI:10.1111/cpr.70056] 11. Gui L, Chen K, Yan J, Chen P, Gao WQ, Ma B (2025) Targeting the mevalonate pathway potentiates NUAK1 inhibition-induced immunogenic cell death and antitumor immunity. Cell Rep Med, 6(2):101913. [ DOI:10.1016/j.xcrm.2024.101913] 12. Garg AD, Krysko DV, Verfaillie T, Kaczmarek A, Ferreira GB, Marysael T, et al. (2012) A novel pathway combining calreticulin exposure and ATP secretion in immunogenic cancer cell death. EMBO J, 31: 1062-1079. [ DOI:10.1038/emboj.2011.497] 13. Chen Y, Wang L, Chen N, Tang G (2024) Metformin induces tumor immunogenic cell death in ovarian cancer by activating AMPK pathway. Transl Oncol, 47: 102052. [ DOI:10.1016/j.tranon.2024.102052] 14. Scaffidi P, Misteli T, Bianchi ME (2002) Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature, 418: 191-195. [ DOI:10.1038/nature00858] 15. Zheng L, Zhao Z, Chen L, Yang W, Ercolani G, Qin P, et al. (2025) Astragalin induces immunogenic cell death in liver cancer by targeting NQO2 to promote ROS-mediated endoplasmic reticulum stress pathway. Free Radic Biol Med, 239: 317-335. [ DOI:10.1016/j.freeradbiomed.2025.07.047] 16. Yamamoto J, Han Q, Inubushi S, Sugisawa N, Hamada K, Nishino H, et al. (2020) Histone methylation status of H3K4me3 and H3K9me3 under methionine restriction is unstable in methionine-addicted cancer cells, but stable in normal cells. Biochem Biophys Res Commun, 533(4):1034-1038. [ DOI:10.1016/j.bbrc.2020.09.108] 17. Guéant JL, Oussalah A, Zgheib R, Siblini Y, Hsu SB, Namour F (2020) Genetic, epigenetic and genomic mechanisms of methionine dependency of cancer and tumor-initiating cells: What could we learn from folate and methionine cycles. Biochimie,173: 123-128. [ DOI:10.1016/j.biochi.2020.03.015] 18. Epner DE, Morrow S, Wilcox M, Houghton JL (2002) Nutrient intake and nutritional indexes in adults with metastatic cancer on a phase I clinical trial of dietary methionine restriction. Nutr cancer, 42: 158-166. [ DOI:10.1207/S15327914NC422_2] 19. Fu YM, Zhang H, Ding M, Li YQ, Fu X, Yu ZX, et al. (2006) Selective amino acid restriction targets mitochondria to induce apoptosis of androgen-independent prostate cancer cells. J cell physiol, 209: 522-534. [ DOI:10.1002/jcp.20766] 20. Wang Z, Yip LY, Lee JHJ, Wu Z, Chew HY, Chong PKW, et al. (2019) Methionine is a metabolic dependency of tumor-initiating cells. Nat med, 25: 825-837. [ DOI:10.1038/s41591-019-0423-5] 21. Jiajia D, Yiping W, Enyan J, Shouwu Z, Shuai Y, Xiaojian Z, et al. (2025) Maresin-1 alleviates lipid peroxidation-induced ferroptosis after radiation-induced brain injury in mice through the RORalpha/NRF2 pathway. Exp Neurol, 389:115258. [ DOI:10.1016/j.expneurol.2025.115258] 22. Elkenawy NM, Ghaiad HR, Ibrahim SM, Aziz RK, Rashad E, Eraqi WA (2023) Ubiquinol preserves immune cells in gamma-irradiated rats: Role of autophagy and apoptosis in splenic tissue. Int Immunopharmacol, 123: 110647. [ DOI:10.1016/j.intimp.2023.110647] 23. Paglin S, Lee NY, Nakar C, Fitzgerald M, Plotkin J, Deuel B, Hackett N, McMahill M, Sphicas E, Lampen N, et al. (2005) Rapamycin-sensitive pathway regulates mitochondrial membrane potential, autophagy, and survival in irradiated MCF-7 cells. Cancer Res, 65: 11061-11070. [ DOI:10.1158/0008-5472.CAN-05-1083] 24. Chaachouay H, Ohneseit P, Toulany M, Kehlbach R, Multhoff G, Rodemann HP (2011) Autophagy contributes to resistance of tumor cells to ionizing radiation. Radiother oncol, 99: 287-292. [ DOI:10.1016/j.radonc.2011.06.002] 25. Tseng HC, Liu WS, Tyan YS, Chiang HC, Kuo WH, Chou FP (2011) Sensitizing effect of 3-methyladenine on radiation-induced cytotoxicity in radio-resistant HepG2 cells in-vitro and in tumor xenografts. Chem biol interact, 192: 201-208. [ DOI:10.1016/j.cbi.2011.03.011] 26. Sun T, Li Y, Yang Y, Liu B, Cao Y, Yang W (2022) Enhanced radiation-induced immunogenic cell death activates chimeric antigen receptor T cells by targeting CD39 against glioblastoma. Cell Death Dis, 13(10): 875. [ DOI:10.1038/s41419-022-05319-1] 27. Yang W, Xiu Z, He Y, Huang W, Li Y, Sun T (2020) Bip inhibition in glioma stem cells promotes radiation-induced immunogenic cell death. Cell Death Dis, 11(9): 786. [ DOI:10.1038/s41419-020-03000-z] 28. Xiu Z, Sun T, Yang Y, He Y, Yang S, Xue X, et al. (2022) Curcumin Enhanced Ionizing Radiation-Induced Immunogenic Cell Death in Glioma Cells through Endoplasmic Reticulum Stress Signaling Pathways. Oxid Med Cell Longev, 2022: 5424411. [ DOI:10.1155/2022/5424411] 29. Huang Y, Dong Y, Zhao J, Zhang L, Kong L, Lu JJ (2019) Comparison of the effects of photon, proton and carbon-ion radiation on the ecto-calreticulin exposure in various tumor cell lines. Ann Transl Med, 7: 542. [ DOI:10.21037/atm.2019.09.128] 30. Saglar E, Unlu S, Babalioglu I, Gokce SC, Mergen H (2014) Assessment of ER stress and autophagy induced by ionizing radiation in both radiotherapy patients and ex-vivo irradiated samples. J Biochem Mol Toxicol, 28: 413-417. [ DOI:10.1002/jbt.21579] 31. Michaud M, Martins I, Sukkurwala AQ, Adjemian S, Ma Y, Pellegatti P, et al. (2011) Autophagy-dependent anticancer immune responses induced by chemotherapeutic agents in mice. Science, 334: 1573-1577. [ DOI:10.1126/science.1208347] 32. Martins I, Michaud M, Sukkurwala AQ, Adjemian S, Ma Y, Shen S, et al. (2012) Premortem autophagy determines the immunogenicity of chemotherapy-induced cancer cell death. Autophagy, 8: 413-415. [ DOI:10.4161/auto.19009] |
|
| Send email to the article author |
|
|
|
| Add your comments about this article |
|
|
|
|
Yang S, Qin H, Jiang X, Xue X, Tan H, Wang B, et al . Methionine deprivation enhances the radiosensitivity of glioma cells and promotes ionizing radiation-induced immunogenic cell death via the endoplasmic reticulum stress signaling pathway. Int J Radiat Res 2026; 24 (3) :627-639 URL: http://ijrr.com/article-1-7177-en.html
|
