Inhibition of the oncogenic fusion protein EWS-FLI1 causes G(2)-M cell cycle arrest and enhanced vincristine sensitivity in Ewing's sarcoma.
Inhibition of the oncogenic fusion protein EWS-FLI1 causes G(2)-M cell cycle arrest and enhanced vincristine sensitivity in Ewing's sarcoma.
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DOI：
10.1126/scisignal.aam8429
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发表时间：
2017-10-03
影响因子：
7.3
通讯作者：
Toretsky JA
中科院分区：
文献类型：
--
作者：
Zöllner SK;Selvanathan SP;Graham GT;Commins RMT;Hong SH;Moseley E;Parks S;Haladyna JN;Erkizan HV;Dirksen U;Hogarty MD;Üren A;Toretsky JA
尤文氏肉瘤（ES）是一种罕见的高度恶性癌症，生长在骨骼或周围组织中，主要影响青少年和年轻人。由染色体易位产生的RNA结合蛋白EWS和ETS家族转录因子FLI 1（EWS-FLI 1）之间的嵌合融合体涉及通过调节转录和选择性剪接来驱动大多数ES病例。小分子YK-4-279抑制EWS-FLI 1功能并诱导ES细胞凋亡。我们的目的是确定药物的潜在机制和可能增强其抗肿瘤活性的潜在联合疗法。我们测试了69种抗癌药物与YK-4-279的组合，发现长春花生物碱在5种ES细胞系中与YK-4-279表现出协同作用。YK-4-279和长春新碱的组合降低了携带ES异种移植物的小鼠的肿瘤负荷并增加了存活率。我们确定，独立的药物诱导的事件会聚在一起，导致这种协同治疗作用。YK-4-279快速诱导G2-M期阻滞，增加细胞周期蛋白B1的丰度，并减少EWS-FLI 1介导的微管相关蛋白的产生，这使得细胞更容易受到长春新碱引起的微管解聚。YK-4-279降低了编码泛素连接酶UBE 2C的EWS-FLI 1靶基因的表达，这在一定程度上导致了细胞周期蛋白B1的增加。YK-4-279还增加了MCL 1和BCL 2的促凋亡亚型的丰度，推测是通过抑制EWS-FLI 1的选择性剪接，从而促进细胞对长春新碱的反应而死亡。因此，长春新碱和YK-4-279的组合在ES患者中可能是治疗有效的。
Ewing’s sarcoma (ES) is a rare and highly malignant cancer that grows in the bones or surrounding tissues mostly affecting adolescents and young adults. A chimeric fusion between the RNA binding protein EWS and the ETS family transcription factor FLI1 (EWS-FLI1), which is generated from a chromosomal translocation, is implicated in driving most ES cases by modulation of transcription and alternative splicing. The small-molecule YK-4-279 inhibits EWS-FLI1 function and induces apoptosis in ES cells. We aimed to identify both the underlying mechanism of the drug and potential combination therapies that might enhance its antitumor activity. We tested 69 anticancer drugs in combination with YK-4-279 and found that vinca alkaloids exhibited synergy with YK-4-279 in five ES cell lines. The combination of YK-4-279 and vincristine reduced tumor burden and increased survival in mice bearing ES xenografts. We determined that independent drug-induced events converged to cause this synergistic therapeutic effect. YK-4-279 rapidly induced G2-M arrest, increased the abundance of cyclin B1, and decreased EWS-FLI1-mediated generation of microtubule-associated proteins, which rendered cells more susceptible to microtubule depolymerization by vincristine. YK-4-279 reduced the expression of the EWS-FLI1 target gene encoding the ubiquitin ligase UBE2C, which, in part, contributed to the increase in cyclin B1. YK-4-279 also increased the abundance of proapoptotic isoforms of MCL1 and BCL2, presumably through inhibition of alternative splicing by EWS-FLI1, thus promoting cell death in response to vincristine. Thus, a combination of vincristine and YK-4-279 might be therapeutically effective in ES patients.
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影响因子：
3.7
作者：
Eichhorn, Joshua M.;Kothari, Anisha;Chambers, Timothy C.
通讯作者：
Chambers, Timothy C.
影响因子：
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作者：
Hong, Sung-Hyeok;Youbi, Sarah. E.;Toretsky, Jeffrey A.
通讯作者：
Toretsky, Jeffrey A.
影响因子：
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影响因子：
11.4
作者：
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通讯作者：
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作者：
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