UBA1 inhibition contributes radiosensitization of glioblastoma cells via blocking DNA damage repair
Glioblastoma multiforme (GBM) is a brain tumor with high mortality and recurrence rate. Radiotherapy and chemotherapy after surgery are the main treatment options available for GBM. However, patients with glioblastoma have a grave prognosis. The major reason is that most GBM patients are resistant t...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-03-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2023.1073929/full |
| _version_ | 1811158978537717760 |
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| author | Changyong Wu Changyong Wu Yang Shen Yang Shen Lin Shi Lin Shi Lin Shi Junhao Zhang Tongxuan Guo Lingni Zhou Wanzhou Wang Xu Zhang Xu Zhang Rutong Yu Rutong Yu Xuejiao Liu Xuejiao Liu |
| author_facet | Changyong Wu Changyong Wu Yang Shen Yang Shen Lin Shi Lin Shi Lin Shi Junhao Zhang Tongxuan Guo Lingni Zhou Wanzhou Wang Xu Zhang Xu Zhang Rutong Yu Rutong Yu Xuejiao Liu Xuejiao Liu |
| author_sort | Changyong Wu |
| collection | DOAJ |
| description | Glioblastoma multiforme (GBM) is a brain tumor with high mortality and recurrence rate. Radiotherapy and chemotherapy after surgery are the main treatment options available for GBM. However, patients with glioblastoma have a grave prognosis. The major reason is that most GBM patients are resistant to radiotherapy. UBA1 is considered an attractive potential anti-tumor therapeutic target and a key regulator of DNA double-strand break repair and genome replication in human cells. Therefore, we hypothesized that TAK-243, the first-in-class UBA1 inhibitor, might increase GBM sensitivity to radiation. The combined effect of TAK-243 and ionizing radiation on GBM cell proliferation, and colony formation ability was detected using CCK-8, colony formation, and EdU assays. The efficacy of TAK-243 combined with ionizing radiation for GBM was further evaluated in vivo, and the mechanism of TAK-243 sensitizing radiotherapy was preliminarily discussed. The results showed that TAK-243, in combination with ionizing radiation, significantly inhibited GBM cell proliferation, colony formation, cell cycle arrest in the G2/M phase, and increased the proportion of apoptosis. In addition, UBA1 inhibition by TAK-243 substantially increased the radiation-induced γ-H2AX expression and impaired the recruitment of the downstream effector molecule 53BP1. Therefore, TAK-243 inhibited the radiation-induced DNA double-strand break repair and thus inhibited the growth of GBM cells. Our results provided a new therapeutic strategy for improving the radiation sensitivity of GBM and laid a theoretical foundation and experimental basis for further clinical trials. |
| first_indexed | 2024-04-10T05:33:24Z |
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| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-10T05:33:24Z |
| publishDate | 2023-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-68cdefb69568496c92b6a7779ed65f2b2023-03-07T04:24:49ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122023-03-011410.3389/fphar.2023.10739291073929UBA1 inhibition contributes radiosensitization of glioblastoma cells via blocking DNA damage repairChangyong Wu0Changyong Wu1Yang Shen2Yang Shen3Lin Shi4Lin Shi5Lin Shi6Junhao Zhang7Tongxuan Guo8Lingni Zhou9Wanzhou Wang10Xu Zhang11Xu Zhang12Rutong Yu13Rutong Yu14Xuejiao Liu15Xuejiao Liu16Insititute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, ChinaDepartment of Neurosurgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, ChinaInsititute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, ChinaDepartment of Neurosurgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, ChinaInsititute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, ChinaDepartment of Neurosurgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, ChinaDepartment of general surgery, The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, ChinaInsititute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, ChinaInsititute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, ChinaInsititute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, ChinaInsititute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, ChinaInsititute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, ChinaDepartment of Neurosurgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, ChinaInsititute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, ChinaDepartment of Neurosurgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, ChinaInsititute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, ChinaDepartment of Neurosurgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, ChinaGlioblastoma multiforme (GBM) is a brain tumor with high mortality and recurrence rate. Radiotherapy and chemotherapy after surgery are the main treatment options available for GBM. However, patients with glioblastoma have a grave prognosis. The major reason is that most GBM patients are resistant to radiotherapy. UBA1 is considered an attractive potential anti-tumor therapeutic target and a key regulator of DNA double-strand break repair and genome replication in human cells. Therefore, we hypothesized that TAK-243, the first-in-class UBA1 inhibitor, might increase GBM sensitivity to radiation. The combined effect of TAK-243 and ionizing radiation on GBM cell proliferation, and colony formation ability was detected using CCK-8, colony formation, and EdU assays. The efficacy of TAK-243 combined with ionizing radiation for GBM was further evaluated in vivo, and the mechanism of TAK-243 sensitizing radiotherapy was preliminarily discussed. The results showed that TAK-243, in combination with ionizing radiation, significantly inhibited GBM cell proliferation, colony formation, cell cycle arrest in the G2/M phase, and increased the proportion of apoptosis. In addition, UBA1 inhibition by TAK-243 substantially increased the radiation-induced γ-H2AX expression and impaired the recruitment of the downstream effector molecule 53BP1. Therefore, TAK-243 inhibited the radiation-induced DNA double-strand break repair and thus inhibited the growth of GBM cells. Our results provided a new therapeutic strategy for improving the radiation sensitivity of GBM and laid a theoretical foundation and experimental basis for further clinical trials.https://www.frontiersin.org/articles/10.3389/fphar.2023.1073929/fullGBMTAK-243radiosensitizationDNA damage repaircell apoptosis |
| spellingShingle | Changyong Wu Changyong Wu Yang Shen Yang Shen Lin Shi Lin Shi Lin Shi Junhao Zhang Tongxuan Guo Lingni Zhou Wanzhou Wang Xu Zhang Xu Zhang Rutong Yu Rutong Yu Xuejiao Liu Xuejiao Liu UBA1 inhibition contributes radiosensitization of glioblastoma cells via blocking DNA damage repair Frontiers in Pharmacology GBM TAK-243 radiosensitization DNA damage repair cell apoptosis |
| title | UBA1 inhibition contributes radiosensitization of glioblastoma cells via blocking DNA damage repair |
| title_full | UBA1 inhibition contributes radiosensitization of glioblastoma cells via blocking DNA damage repair |
| title_fullStr | UBA1 inhibition contributes radiosensitization of glioblastoma cells via blocking DNA damage repair |
| title_full_unstemmed | UBA1 inhibition contributes radiosensitization of glioblastoma cells via blocking DNA damage repair |
| title_short | UBA1 inhibition contributes radiosensitization of glioblastoma cells via blocking DNA damage repair |
| title_sort | uba1 inhibition contributes radiosensitization of glioblastoma cells via blocking dna damage repair |
| topic | GBM TAK-243 radiosensitization DNA damage repair cell apoptosis |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2023.1073929/full |
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