N6-Isopentenyladenosine Enhances the Radiosensitivity of Glioblastoma Cells by Inhibiting the Homologous Recombination Repair Protein RAD51 Expression
N6-Isopentenyladenosine Enhances the Radiosensitivity of Glioblastoma Cells by Inhibiting the Homologous Recombination Repair Protein RAD51 Expression
复制标题
DOI：
10.3389/fonc.2019.01498
复制
发表时间：
2020-01-14
影响因子：
4.7
通讯作者：
Bifulco, Maurizio
中科院分区：
文献类型：
--
作者：
Navarra, Giovanna;Pagano, Cristina;Bifulco, Maurizio
胶质母细胞瘤是最常见的恶性脑肿瘤之一，由于对电离辐射和dna烷基化剂等治疗方案反应不佳，预后不佳。在我们的研究中，我们研究了n -6-异戊烯基腺苷（iPA）的放射增敏活性，iPA是一种天然修饰的腺苷，含有异戊烯基部分，对胶质母细胞瘤细胞系具有抗增殖作用。我们观察到，电离辐射和微摩尔浓度的iPA共同作用抑制胶质母细胞瘤细胞系的集落形成和活力，但对非恶性人类细胞没有作用。联合治疗通过抑制同源重组修复过程中的关键分子RAD51的表达和辐照诱导的病灶形成，显著减弱辐射诱导的DNA损伤的修复，导致持续的DNA损伤，表现为γ - h2ax病灶的增加。放射增敏效应还依赖于抑制STAT5a/b的激活，这对RAD51的表达至关重要，这表明iPA在电离辐射暴露后调节STAT5a/b-RAD51轴。总的来说，这些数据表明iPA在机制水平上通过RAD51抑制作用，可能作为一种有前途的放射增敏剂，值得在前瞻性临床试验中进一步评估。
Glioblastoma is among the most common malignant brain tumors and has a dismal prognosis due to the poor response to therapeutic regimens such as ionizing radiation and DNA-alkylating agents. In our study, we investigated the radiosensitizing activity of the N-6-isopentenyladenosine (iPA), an naturally modified adenosine harboring an isopenenyl moiety, which shows antiproliferative effects on glioblastoma cell lines. We observed that co-treatment with ionizing radiation and iPA at micromolar concentration inhibited colony formation and viability of glioblastoma cell lines but not of non-malignant human cells. The combined treatment significantly attenuated the repair of radiation-induced DNA damage by inhibiting both the expression and irradiation-induced foci formation of RAD51, a key player in the homologous recombination repair process, leading to persistent DNA damage, as reflected by an increase of gamma-H2AX foci. The radiosensitizing effect relied also on the inhibition of STAT5a/b activation, which is crucial for RAD51 expression, suggesting that iPA modulates the STAT5a/b-RAD51 axis following exposure to ionizing radiation. Overall, these data suggest that iPA, by acting through RAD51 inhibition at the mechanistic level, could function as a promising radiosensitizing agent and warrants further evaluation in prospective clinical trials.