尼拉帕利通过DDX21增强胶质母细胞瘤放射敏感性

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Abstract Objective： To explore the feasibility and mechanism of the poly(ADP-ribose)polymerase (PARP) inhibitor niraparib as a radiosensitizer for glioblastoma (GBM). Methods： Bioinformatics analysis was used to reveal the mechanism of PARP inhibitors in glioma and its correlation with radiotherapy. CCK-8 was used to determine the optimal concentration and treatment time of niraparib in GBM cells (A172, U251 and U87). A clonogenic assay was used to detect the radiosensitivity of GBM cells to niraparib. Flow cytometry was used to detect the effect of niraparb combined with radiotherapy on GBM cell cycle. Western blotting was used to detect the impact of niraparib combined with radiotherapy on the expression of DExD-box RNA helicase (DDX21) protein. Immunofluorescence was used to detect the effect of niraparib combined with radiotherapy on the localization of DDX21 in the nucleus of GBM cells. Results： Pathways relevant to ribosome biosynthesis and functions was found to be responsible for cytotoxicity of niraparib in 519 tumor cell lines. Homologous recombination repair ability was highly positively correlated with ribosomal biosynthesis ability in 44 solid tumor cell lines. Moreover, the IC50 of niraparib in A172 and U87 cell lines were (10.77±3.31)μmol/L and (32.37±2.84)μmol/L respectively. The dose enhancement factor (DEF37) of A172 cells was 1.99 and 2.17 at the concentrations of niraparib at 348 nmol/L and 1 044 nmol/L, respectively, and the DEF37 of U87 cells was 1.10 and 1.44 at concentrations of 1 056 nmol/L and 3 169 nmol/L, respectively. Niraparib exerted radiosensization effects on A172 and U87 cells of p53 wildtype, but not on U251 cell of p53 mutant. Niraparib increased radiosensitivity through G2/M phase arrest in A172 and U87 cellls. Finally, in U87 cells, niraparib combined with irradiation didn′t affect the protein expression of DDX21, but it could lead to the translocation of DDX21 from the nucleolus to the nucleoplasm. Knockdown of DDX21 in U87 cells with high expression of DDX21 resulted radiotherapy resistance, and niraparib still has radiosensitization effect in U87 cells after DDX21 knockdown. Conclusions： Niraparib affected ribosome biosynthesis via translocation of DDX21 from the nucleolus to the nucleoplasm, causing the cell cycle to block the G2/M stage, thus increasing the radiosensitivity of U87 cells.

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Received: 18 December 2023

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http://zzs.ujs.edu.cn/xbyxb/EN/ OR http://zzs.ujs.edu.cn/xbyxb/EN/Y2024/V34/I05/395

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