UBA1 inhibition contributes radiosensitization of glioblastoma cells via blocking DNA damage repair.
UBA1 inhibition contributes radiosensitization of glioblastoma cells via blocking DNA damage repair.
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DOI：
10.3389/fphar.2023.1073929
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发表时间：
2023
影响因子：
5.6
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中科院分区：
文献类型：
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多形性胶质母细胞瘤（GBM）是一种高死亡率和复发率的脑肿瘤。术后放疗和化疗是GBM的主要治疗选择。然而，患有胶质母细胞瘤的患者具有严重的预后。主要原因是大多数GBM患者对放射治疗有抵抗力。UBA 1被认为是一个有吸引力的潜在抗肿瘤治疗靶点，是人类细胞DNA双链断裂修复和基因组复制的关键调控因子。因此，我们假设TAK-243（首个UBA 1抑制剂）可能会增加GBM对辐射的敏感性。使用CCK-8、集落形成和EdU试验检测TAK-243和电离辐射对GBM细胞增殖和集落形成能力的联合作用。进一步在体内评价TAK-243联合电离辐射对GBM的疗效，并初步探讨TAK-243增敏放疗的机制。结果表明，TAK-243与电离辐射联合使用可显著抑制GBM细胞增殖、集落形成、细胞周期停滞在G2/M期，并增加凋亡比例。此外，TAK-243对UBA 1的抑制显著增加了辐射诱导的γ-H2 AX表达，并损害了下游效应分子53 BP 1的募集。因此，TAK-243抑制辐射诱导的DNA双链断裂修复，从而抑制GBM细胞的生长。本研究为提高GBM的放射敏感性提供了新的治疗策略，为进一步的临床试验奠定了理论基础和实验基础。
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.
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