Inhibition of deubiquitinases primes glioblastoma cells to apoptosis in vitro and in vivo.
Inhibition of deubiquitinases primes glioblastoma cells to apoptosis in vitro and in vivo.
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DOI：
10.18632/oncotarget.7302
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发表时间：
2016-03-15
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影响因子：
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通讯作者：
Siegelin MD
中科院分区：
文献类型：
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作者：
Karpel-Massler G;Banu MA;Shu C;Halatsch ME;Westhoff MA;Bruce JN;Canoll P;Siegelin MD
它仍然是肿瘤学的一个挑战，以确定新的药物方案，以有效地解决胶质母细胞瘤，最常见的原发性脑肿瘤在成人。在这里，我们通过利用小分子抑制剂WP 1130来靶向用于胶质母细胞瘤治疗的去泛素化酶，WP 1130已被表征为干扰Usp 9 X功能的去泛素化酶抑制剂。表达分析数据证实，与正常脑组织相比，Usp 9 X表达在胶质母细胞瘤中增加，表明其作为治疗剂的潜力。一致地，增加浓度的WP 1130降低了已建立的患者来源的异种移植物（PDX）和干细胞样胶质母细胞瘤细胞的细胞活力。Usp 9 X的特异性下调降低胶质母细胞瘤细胞的活力，模拟WP 1130的作用。在机制上，WP 1130诱发细胞凋亡并增加半胱天冬酶的活化。此外，WP 1130和靶向Usp 9 X的siRNAs降低了抗凋亡Bcl-2家族成员以及凋亡蛋白抑制剂XIAP和生存素的表达。药理学和遗传干扰Usp 9 X有效地敏化胶质母细胞瘤细胞的内在和外在的凋亡刺激。此外，用WP 1130单次处理在胶质母细胞瘤的原位前神经鼠模型中引起抗胶质瘤活性。最后，WP 1130和ABT 263的组合治疗比每种试剂自身在体内更有效地抑制肿瘤生长，而没有可检测的副作用或器官毒性。总之，这些结果表明，靶向去泛素化酶治疗胶质瘤是可行和有效的。
It remains a challenge in oncology to identify novel drug regimens to efficiently tackle glioblastoma, the most common primary brain tumor in adults. Here, we target deubiquitinases for glioblastoma therapy by utilizing the small-molecule inhibitor WP1130 which has been characterized as a deubiquitinase inhibitor that interferes with the function of Usp9X. Expression analysis data confirm that Usp9X expression is increased in glioblastoma compared to normal brain tissue indicating its potential as a therapeutic. Consistently, increasing concentrations of WP1130 decrease the cellular viability of established, patient-derived xenograft (PDX) and stem cell-like glioblastoma cells. Specific down-regulation of Usp9X reduces viability in glioblastoma cells mimicking the effects of WP1130. Mechanistically, WP1130 elicits apoptosis and increases activation of caspases. Moreover, WP1130 and siRNAs targeting Usp9X reduce the expression of anti-apoptotic Bcl-2 family members and Inhibitor of Apoptosis Proteins, XIAP and Survivin. Pharmacological and genetic interference with Usp9X efficiently sensitized glioblastoma cells to intrinsic and extrinsic apoptotic stimuli. In addition, single treatment with WP1130 elicited anti-glioma activity in an orthotopic proneural murine model of glioblastoma. Finally, the combination treatment of WP1130 and ABT263 inhibited tumor growth more efficiently than each reagent by its own in vivo without detectable side effects or organ toxicity. Taken together, these results suggest that targeting deubiquitinases for glioma therapy is feasible and effective.