Carfilzomib promotes Iodine-125 seed radiation-induced apoptosis, paraptosis, and ferroptosis in esophageal squamous cell carcinoma by aggravating endoplasmic reticulum stress
Iodine-125 (125I) seed brachytherapy has been applied to treat various malignant tumors such as esophageal cancer, however, radioresistance can reduce its efficacy. Endoplasmic reticulum stress (ERS) and subsequent unfolded protein response (UPR) is one of the core mechanisms of 125I seed radiation-...
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Elsevier
2025-07-01
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| Series: | Translational Oncology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S193652332500124X |
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| author | Chao Wang Yin-Lin Zha Hao Wang Bai Sun Wei-Guang Qiang Ye Yuan Hong-Bing Shi Wen-Wei Hu |
| author_facet | Chao Wang Yin-Lin Zha Hao Wang Bai Sun Wei-Guang Qiang Ye Yuan Hong-Bing Shi Wen-Wei Hu |
| author_sort | Chao Wang |
| collection | DOAJ |
| description | Iodine-125 (125I) seed brachytherapy has been applied to treat various malignant tumors such as esophageal cancer, however, radioresistance can reduce its efficacy. Endoplasmic reticulum stress (ERS) and subsequent unfolded protein response (UPR) is one of the core mechanisms of 125I seed radiation-induced cell death, thus aggravating ERS has been considered a promising sensitization strategy. Herein, we show that combination therapy of an irreversible proteasome inhibitor carfilzomib (CFZ) and 125I seed radiation displayed strong anti-tumor effect on esophageal squamous cell carcinoma (ESCC). Mechanistically, ERS and UPR regulated multiple cell death modalities induced by the combination therapy, including apoptosis, paraptosis, and ferroptosis. 125I seed radiation induced reactive oxygen species (ROS) production, DNA damage, p53 activation, and apoptosis. CFZ promoted ROS production, and augmented 125I seed radiation-induced apoptosis via the mitochondrial pathway, which was mediated by the UPR-C/EBP homologous protein (CHOP) pathway and was independent of the p53 pathway. CFZ enhanced 125I seed radiation-induced intracellular Ca2+ overload, protein ubiquitination, ERS, and UPR, consequently promoting paraptosis. 125I seed radiation induced accumulation of intracellular Fe2+ and lipid peroxides but upregulated the expression of ferroptosis inhibitors, SLC7A11 and glutathione peroxidase 4 (GPX4). The combination therapy promoted ferroptosis by enhancing the accumulation of intracellular Fe2+ and downregulating GPX4 expression. The mouse experiment demonstrated that CFZ can promote the efficacy of 125I seed radiation with good tolerance. Our findings suggest that combination therapy of 125I seed radiation and CFZ is associated with multiple cell death modalities and may serve as a promising therapeutic strategy for ESCC. |
| format | Article |
| id | doaj-art-a2a6cebdcac94fd89bb7d7cd1a8a0cee |
| institution | OA Journals |
| issn | 1936-5233 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Translational Oncology |
| spelling | doaj-art-a2a6cebdcac94fd89bb7d7cd1a8a0cee2025-08-20T01:52:55ZengElsevierTranslational Oncology1936-52332025-07-015710239310.1016/j.tranon.2025.102393Carfilzomib promotes Iodine-125 seed radiation-induced apoptosis, paraptosis, and ferroptosis in esophageal squamous cell carcinoma by aggravating endoplasmic reticulum stressChao Wang0Yin-Lin Zha1Hao Wang2Bai Sun3Wei-Guang Qiang4Ye Yuan5Hong-Bing Shi6Wen-Wei Hu7Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, PR ChinaDepartment of Radiation Oncology, the Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, PR ChinaDepartment of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, PR ChinaDepartment of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, PR ChinaDepartment of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, PR ChinaDepartment of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, PR ChinaDepartment of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, PR China; Corresponding authors.Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, PR China; Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, PR China; Corresponding authors.Iodine-125 (125I) seed brachytherapy has been applied to treat various malignant tumors such as esophageal cancer, however, radioresistance can reduce its efficacy. Endoplasmic reticulum stress (ERS) and subsequent unfolded protein response (UPR) is one of the core mechanisms of 125I seed radiation-induced cell death, thus aggravating ERS has been considered a promising sensitization strategy. Herein, we show that combination therapy of an irreversible proteasome inhibitor carfilzomib (CFZ) and 125I seed radiation displayed strong anti-tumor effect on esophageal squamous cell carcinoma (ESCC). Mechanistically, ERS and UPR regulated multiple cell death modalities induced by the combination therapy, including apoptosis, paraptosis, and ferroptosis. 125I seed radiation induced reactive oxygen species (ROS) production, DNA damage, p53 activation, and apoptosis. CFZ promoted ROS production, and augmented 125I seed radiation-induced apoptosis via the mitochondrial pathway, which was mediated by the UPR-C/EBP homologous protein (CHOP) pathway and was independent of the p53 pathway. CFZ enhanced 125I seed radiation-induced intracellular Ca2+ overload, protein ubiquitination, ERS, and UPR, consequently promoting paraptosis. 125I seed radiation induced accumulation of intracellular Fe2+ and lipid peroxides but upregulated the expression of ferroptosis inhibitors, SLC7A11 and glutathione peroxidase 4 (GPX4). The combination therapy promoted ferroptosis by enhancing the accumulation of intracellular Fe2+ and downregulating GPX4 expression. The mouse experiment demonstrated that CFZ can promote the efficacy of 125I seed radiation with good tolerance. Our findings suggest that combination therapy of 125I seed radiation and CFZ is associated with multiple cell death modalities and may serve as a promising therapeutic strategy for ESCC.http://www.sciencedirect.com/science/article/pii/S193652332500124XIodine-125CarfilzomibApoptosisFerroptosisEsophageal cancer |
| spellingShingle | Chao Wang Yin-Lin Zha Hao Wang Bai Sun Wei-Guang Qiang Ye Yuan Hong-Bing Shi Wen-Wei Hu Carfilzomib promotes Iodine-125 seed radiation-induced apoptosis, paraptosis, and ferroptosis in esophageal squamous cell carcinoma by aggravating endoplasmic reticulum stress Translational Oncology Iodine-125 Carfilzomib Apoptosis Ferroptosis Esophageal cancer |
| title | Carfilzomib promotes Iodine-125 seed radiation-induced apoptosis, paraptosis, and ferroptosis in esophageal squamous cell carcinoma by aggravating endoplasmic reticulum stress |
| title_full | Carfilzomib promotes Iodine-125 seed radiation-induced apoptosis, paraptosis, and ferroptosis in esophageal squamous cell carcinoma by aggravating endoplasmic reticulum stress |
| title_fullStr | Carfilzomib promotes Iodine-125 seed radiation-induced apoptosis, paraptosis, and ferroptosis in esophageal squamous cell carcinoma by aggravating endoplasmic reticulum stress |
| title_full_unstemmed | Carfilzomib promotes Iodine-125 seed radiation-induced apoptosis, paraptosis, and ferroptosis in esophageal squamous cell carcinoma by aggravating endoplasmic reticulum stress |
| title_short | Carfilzomib promotes Iodine-125 seed radiation-induced apoptosis, paraptosis, and ferroptosis in esophageal squamous cell carcinoma by aggravating endoplasmic reticulum stress |
| title_sort | carfilzomib promotes iodine 125 seed radiation induced apoptosis paraptosis and ferroptosis in esophageal squamous cell carcinoma by aggravating endoplasmic reticulum stress |
| topic | Iodine-125 Carfilzomib Apoptosis Ferroptosis Esophageal cancer |
| url | http://www.sciencedirect.com/science/article/pii/S193652332500124X |
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