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

Changyong Wu; Yang Shen; Lin Shi; Junhao Zhang; Tongxuan Guo; Lingni Zhou; Wanzhou Wang; Xu Zhang; Rutong Yu; Xuejiao Liu

doi:10.3389/fphar.2023.1073929

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

Front Pharmacol. 2023 Mar 7:14:1073929. doi: 10.3389/fphar.2023.1073929. eCollection 2023.

Authors

Changyong Wu^{1

2}, Yang Shen^{1

2}, Lin Shi^{1

2

3}, Junhao Zhang¹, Tongxuan Guo¹, Lingni Zhou¹, Wanzhou Wang¹, Xu Zhang^{1

2}, Rutong Yu^{1

2}, Xuejiao Liu^{1

2}

Affiliations

¹ Insititute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, China.
² Department of Neurosurgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.
³ Department of general surgery, The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.

Abstract

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.

Keywords: DNA damage repair; GBM; TAK-243; cell apoptosis; radiosensitization.

Grants and funding

This research was supported by the following grants: The National Natural Science Foundation of China (No. 81972345); the Postgraduate Research and Practice Innovation Program of Jiangsu Province (KYCX21_2684); The Medical Science and Technology Innovation Project of Xuzhou Municipal Health Commission (XWKYHT20220106); Jiangsu Province University Key Laboratory Open Project (XZSYSKF2020003); Xuzhou Medical University Affiliated Hospital Development Fund Project (XYFY2020004).