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

by Selleckchem | Jul 29 2023

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.

Comments:

The research described proposes the use of TAK-243, a UBA1 inhibitor, as a potential therapeutic strategy to enhance the sensitivity of glioblastoma multiforme (GBM) to radiotherapy. The study aimed to investigate the combined effect of TAK-243 and ionizing radiation on GBM cell proliferation and colony formation ability, both in vitro and in vivo.

To evaluate the efficacy of the combination treatment, several assays were performed. The CCK-8 assay, which measures cell viability, showed that the combination of TAK-243 and ionizing radiation significantly inhibited GBM cell proliferation. The colony formation assay also demonstrated a decrease in the colony-forming ability of GBM cells when treated with the combination therapy. Additionally, the EdU assay was conducted to assess the impact on cell cycle progression, revealing cell cycle arrest in the G2/M phase and an increase in apoptosis.

Further investigation was carried out to understand the underlying mechanisms of TAK-243 in sensitizing GBM cells to radiation. The study found that UBA1 inhibition by TAK-243 led to increased expression of γ-H2AX, a marker of DNA double-strand breaks, in response to radiation. Moreover, the recruitment of 53BP1, an important downstream molecule involved in DNA repair, was impaired by TAK-243 treatment. These findings suggest that TAK-243 inhibited radiation-induced DNA double-strand break repair, leading to the suppression of GBM cell growth.

The results obtained from this study propose TAK-243 as a potential therapeutic strategy to improve the radiation sensitivity of GBM. By targeting UBA1 and impairing DNA repair mechanisms, TAK-243 demonstrated enhanced efficacy when combined with ionizing radiation. These findings provide a theoretical basis and experimental evidence for potential clinical trials exploring the use of TAK-243 in the treatment of GBM. However, it is important to note that further research and clinical validation are necessary before this therapeutic strategy can be widely implemented.