GLS2 inhibition synergizes with copper to reprogram TCA cycle for cuproptosis-driven radiosensitization in esophageal cancer
Abstract Esophageal squamous cell carcinoma (ESCC) is notorious for its poor prognosis. In the present study, the role of glutaminase 2 (GLS2) and copper (Cu) in the radiosensitivity of ESCC was explored. Both in vitro and in vivo experiments were conducted, and the results demonstrated that the kno...
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| Format: | Article |
| Language: | English |
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BMC
2025-04-01
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| Series: | Experimental Hematology & Oncology |
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| Online Access: | https://doi.org/10.1186/s40164-025-00653-4 |
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| author | Wang Jing Wenhao Wang Yi Ding Renya Zeng Hui Zhu Zhichao Kang Alei Feng Zhe Yang |
| author_facet | Wang Jing Wenhao Wang Yi Ding Renya Zeng Hui Zhu Zhichao Kang Alei Feng Zhe Yang |
| author_sort | Wang Jing |
| collection | DOAJ |
| description | Abstract Esophageal squamous cell carcinoma (ESCC) is notorious for its poor prognosis. In the present study, the role of glutaminase 2 (GLS2) and copper (Cu) in the radiosensitivity of ESCC was explored. Both in vitro and in vivo experiments were conducted, and the results demonstrated that the knockdown of GLS2 could suppress cell proliferation and augment the sensitivity to radiotherapy (RT). The addition of Cu influenced cell viability and radiosensitivity. Notably, under normal GLS2 expression status, exogenous Cu augmented RT sensitivity without triggering cuproptosis. Mechanistically, the suppression of GLS2 interacted with Cu to downregulate lipoic acid synthase and dihydrolipoamide S-succinyltransferase, resulting in the reduction of the activity of α-ketoglutarate dehydrogenase complex and the obstruction of the tricarboxylic acid cycle, ultimately leading to the enhancement of RT sensitivity. These findings emphasize the significance of cuproptosis in ESCC radiotherapy and provide potential directions for therapeutic strategies. |
| format | Article |
| id | doaj-art-b0b62a4c211a4b3ca4bb37d3f1eebfc0 |
| institution | OA Journals |
| issn | 2162-3619 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Experimental Hematology & Oncology |
| spelling | doaj-art-b0b62a4c211a4b3ca4bb37d3f1eebfc02025-08-20T02:16:56ZengBMCExperimental Hematology & Oncology2162-36192025-04-011411510.1186/s40164-025-00653-4GLS2 inhibition synergizes with copper to reprogram TCA cycle for cuproptosis-driven radiosensitization in esophageal cancerWang Jing0Wenhao Wang1Yi Ding2Renya Zeng3Hui Zhu4Zhichao Kang5Alei Feng6Zhe Yang7Shandong Provincial Hospital Affiliated to Shandong First Medical UniversityDepartment of Medical Oncology, Affiliated Hospital of Shandong Second Medical UniversityDepartment of Radiation Oncology, Shandong Provincial HospitalDepartment of Radiation Oncology, Shandong Provincial HospitalDepartment of Radiation Oncology, Shandong Cancer Hospital Affiliated to Shandong First Medical UniversityDepartment of Radiation Oncology, Shandong Provincial HospitalDepartment of Radiation Oncology, Shandong Provincial HospitalDepartment of Radiation Oncology, Shandong Provincial HospitalAbstract Esophageal squamous cell carcinoma (ESCC) is notorious for its poor prognosis. In the present study, the role of glutaminase 2 (GLS2) and copper (Cu) in the radiosensitivity of ESCC was explored. Both in vitro and in vivo experiments were conducted, and the results demonstrated that the knockdown of GLS2 could suppress cell proliferation and augment the sensitivity to radiotherapy (RT). The addition of Cu influenced cell viability and radiosensitivity. Notably, under normal GLS2 expression status, exogenous Cu augmented RT sensitivity without triggering cuproptosis. Mechanistically, the suppression of GLS2 interacted with Cu to downregulate lipoic acid synthase and dihydrolipoamide S-succinyltransferase, resulting in the reduction of the activity of α-ketoglutarate dehydrogenase complex and the obstruction of the tricarboxylic acid cycle, ultimately leading to the enhancement of RT sensitivity. These findings emphasize the significance of cuproptosis in ESCC radiotherapy and provide potential directions for therapeutic strategies.https://doi.org/10.1186/s40164-025-00653-4CuproptosisEsophageal cancerRadiotherapyCancer metabolismGLS2 |
| spellingShingle | Wang Jing Wenhao Wang Yi Ding Renya Zeng Hui Zhu Zhichao Kang Alei Feng Zhe Yang GLS2 inhibition synergizes with copper to reprogram TCA cycle for cuproptosis-driven radiosensitization in esophageal cancer Experimental Hematology & Oncology Cuproptosis Esophageal cancer Radiotherapy Cancer metabolism GLS2 |
| title | GLS2 inhibition synergizes with copper to reprogram TCA cycle for cuproptosis-driven radiosensitization in esophageal cancer |
| title_full | GLS2 inhibition synergizes with copper to reprogram TCA cycle for cuproptosis-driven radiosensitization in esophageal cancer |
| title_fullStr | GLS2 inhibition synergizes with copper to reprogram TCA cycle for cuproptosis-driven radiosensitization in esophageal cancer |
| title_full_unstemmed | GLS2 inhibition synergizes with copper to reprogram TCA cycle for cuproptosis-driven radiosensitization in esophageal cancer |
| title_short | GLS2 inhibition synergizes with copper to reprogram TCA cycle for cuproptosis-driven radiosensitization in esophageal cancer |
| title_sort | gls2 inhibition synergizes with copper to reprogram tca cycle for cuproptosis driven radiosensitization in esophageal cancer |
| topic | Cuproptosis Esophageal cancer Radiotherapy Cancer metabolism GLS2 |
| url | https://doi.org/10.1186/s40164-025-00653-4 |
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