Cancer-Specific Requirement for BUB1B/BUBR1 in Human Brain Tumor Isolates and Genetically Transformed Cells
Cancer-Specific Requirement for BUB1B/BUBR1 in Human Brain Tumor Isolates and Genetically Transformed Cells
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DOI：
10.1158/2159-8290.cd-12-0353
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发表时间：
2013-02-01
期刊：
影响因子：
28.2
通讯作者：
Paddison, Patrick J.
中科院分区：
文献类型：
--
作者：
Ding, Yu;Hubert, Christopher G.;Paddison, Patrick J.
为了确定多形性胶质母细胞瘤的新候选治疗靶点，我们结合功能遗传学和胶质母细胞瘤网络模型来确定患者源性脑肿瘤启动细胞（BTIC）生长所需的激酶，但这些激酶对于增殖的人类神经干细胞（NSC）是必不可少的。这种方法产生了BUB1B/BUBR1，一个关键的有丝分裂纺锤体检查点参与者，作为评分最高的胶质母细胞瘤致死激酶。在体外和体内，敲低BUB1B抑制BTIC分离株的增殖，而不影响NSCs或星形胶质细胞的增殖。机制研究表明，BUB1B的gle2b结合序列（GLEBS）结构域活性是抑制胶质母细胞瘤分离物和姊妹KT动力学改变的遗传转化细胞中致命的着丝点微管（KT- mt）附着缺陷所必需的，这可能有利于KT- mt的不稳定性。这些结果表明，胶质母细胞瘤肿瘤对BUB1B有额外的需求，以抑制KT功能改变的致命后果，并进一步表明姐妹KT测量可能预测癌症对BUB1B抑制的特异性敏感性，以及可能影响KT- mt稳定性的其他有丝分裂靶点。意义：胶质母细胞瘤是最常见、最具侵袭性的脑肿瘤，目前尚无有效的治疗方法。我们的研究结果表明，靶向BUB1B的GLEBS结构域活性可能为胶质母细胞瘤的治疗提供了一个窗口，因为GLEBS结构域在未转化的细胞中是不必要的。此外，研究结果进一步表明，中期姐妹KT距离可以预测针对KT功能的抗癌治疗的敏感性。癌症越是加大;3 (2);198 - 211。(c) 2012年aacr。参见Venere等人的相关评论，第141页。
To identify new candidate therapeutic targets for glioblastoma multiforme, we combined functional genetics and glioblastoma network modeling to identify kinases required for the growth of patient-derived brain tumor-initiating cells (BTIC) but that are dispensable to proliferating human neural stem cells (NSC). This approach yielded BUB1B/BUBR1, a critical mitotic spindle checkpoint player, as the top-scoring glioblastoma lethal kinase. Knockdown of BUB1B inhibited expansion of BTIC isolates, both in vitro and in vivo, without affecting proliferation of NSCs or astrocytes. Mechanistic studies revealed that BUB1B's GLE2p-binding sequence (GLEBS) domain activity is required to suppress lethal kinetochore-microtubule (KT-MT) attachment defects in glioblastoma isolates and genetically transformed cells with altered sister KT dynamics, which likely favor KT-MT instability. These results indicate that glioblastoma tumors have an added requirement for BUB1B to suppress lethal consequences of altered KT function and further suggest that sister KT measurements may predict cancer-specific sensitivity to BUB1B inhibition and perhaps other mitotic targets that affect KT-MT stability.SIGNIFICANCE: Currently, no effective therapies are available for glioblastoma, the most frequent and aggressive brain tumor. Our results suggest that targeting the GLEBS domain activity of BUB1B may provide a therapeutic window for glioblastoma, as the GLEBS domain is nonessential in untransformed cells. Moreover, the results further suggest that sister KT distances at metaphase may predict sensitivity to anticancer therapeutics targeting KT function. Cancer Discov; 3(2); 198-211. (C) 2012 AACR. See related commentary by Venere et al., p. 141.