UBA1 inhibition contributes radiosensitization of glioblastoma cells via blocking DNA damage repair

• Published in: Frontiers in pharmacology Vol. 14; p. 1073929
• Main Authors: Wu, Changyong, Shen, Yang, Shi, Lin, Zhang, Junhao, Guo, Tongxuan, Zhou, Lingni, Wang, Wanzhou, Zhang, Xu, Yu, Rutong, Liu, Xuejiao
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 07.03.2023
• Subjects: cell apoptosis; DNA damage repair; GBM; Pharmacology; radiosensitization; TAK-243; cell apoptosis; DNA damage repair; GBM; TAK-243; radiosensitization
• ISSN: 1663-9812; 1663-9812
• DOI: 10.3389/fphar.2023.1073929

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 , 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.