BUB1 and BUBR1 inhibition decreases proliferation and colony formation, and enhances radiation sensitivity in pediatric glioblastoma cells
BUB1 and BUBR1 inhibition decreases proliferation and colony formation, and enhances radiation sensitivity in pediatric glioblastoma cells
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DOI：
10.1007/s00381-013-2175-8
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发表时间：
2013-12-01
影响因子：
1.4
通讯作者：
Tone, Luiz Gonzaga
中科院分区：
文献类型：
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作者：
Morales, Andressa Gois;Pezuk, Julia Alejandra;Tone, Luiz Gonzaga
胶质母细胞瘤（GBM）是一种侵袭性强、致死性高、预后差的脑肿瘤。尽管有新的治疗策略，但在大多数情况下，患者的中位生存期仍低于1年。BUB基因家族的表达已被证明在各种实体瘤中发生改变，指出其作为推定的治疗靶点的作用。本研究旨在检测BUB 1、BUB 3和BUBR 1基因在胶质母细胞瘤中的表达谱，并分析BUB 1和BUBR 1抑制剂联合或不联合替莫唑胺和放射对儿童SF 188 GBM细胞系的影响。使用siRNA评估BUB 1和BUBR 1抑制的效果。细胞凋亡，细胞增殖，细胞周期动力学，微核形成和克隆形成能力后，BUB 1和BUBR 1抑制进行了分析。此外，基因抑制和辐射或替莫唑胺（TMZ）治疗的组合效应通过增殖和克隆形成能力assays.We报告的上调BUB 1和BUBR 1的表达和下调BUB 3的GBM样品和细胞系相比，白色物质样品（p < 0.05）。观察到BUB 1和BUBR 1抑制后细胞增殖和集落形成减少，沿着微核形成增加。与TMZ的组合也引起细胞周期停滞和细胞凋亡增加。此外，我们的研究结果表明，BUB 1和BUBR 1抑制剂可使SF 188细胞对γ射线敏感，表现为生长减少和集落形成能力消失; BUB 1和BUBR 1抑制剂可降低增殖，并对儿科GBM细胞显示出放射增敏作用，这可能会改善这种毁灭性肿瘤的治疗策略。总的来说，这些发现突出了BUB 1和BUBR 1作为胶质母细胞瘤治疗的假定治疗靶点的潜力。
Glioblastoma (GBM) is a very aggressive and lethal brain tumor with poor prognosis. Despite new treatment strategies, patients' median survival is still lower than 1 year in most cases. The expression of the BUB gene family has demonstrated to be altered in a variety of solid tumors, pointing to a role as putative therapeutic target. The purpose of this study was to determine BUB1, BUB3, and BUBR1 gene expression profiles in glioblastoma and to analyze the effects of BUB1 and BUBR1 inhibition combined or not with Temozolomide and radiation in the pediatric SF188 GBM cell line.For gene expression analysis, 8 cell lines and 18 tumor samples were used. The effect of BUB1 and BUBR1 inhibition was evaluated using siRNA. Apoptosis, cell proliferation, cell cycle kinetics, micronuclei formation, and clonogenic capacity were analyzed after BUB1 and BUBR1 inhibition. Additionally, combinatorial effects of gene inhibition and radiation or Temozolomide (TMZ) treatment were evaluated through proliferation and clonogenic capacity assays.We report the upregulation of BUB1 and BUBR1 expression and the downregulation of BUB3 in GBM samples and cell lines when compared to white matter samples (p < 0.05). Decreased cell proliferation and colony formation after BUB1 and BUBR1 inhibition were observed, along with increased micronuclei formation. Combinations with TMZ also caused cell cycle arrest and increased apoptosis. Moreover, our results demonstrate that BUB1 and BUBR1 inhibition sensitized SF188 cells to gamma-irradiation as shown by decreased growth and abrogation of colony formation capacity.BUB1 and BUBR1 inhibition decreases proliferation and shows radiosensitizing effects on pediatric GBM cells, which could improve treatment strategies for this devastating tumor. Collectively, these findings highlight the potentials of BUB1 and BUBR1 as putative therapeutic targets for glioblastoma treatment.