γ-Secretase inhibitor I inhibits neuroblastoma cells, with NOTCH and the proteasome among its targets.
γ-Secretase inhibitor I inhibits neuroblastoma cells, with NOTCH and the proteasome among its targets.
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DOI：
10.18632/oncotarget.11715
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发表时间：
2016-09-27
期刊：
影响因子：
--
通讯作者：
Beltinger C
中科院分区：
文献类型：
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作者：
Dorneburg C;Goß AV;Fischer M;Roels F;Barth TF;Berthold F;Kappler R;Oswald F;Siveke JT;Molenaar JJ;Debatin KM;Beltinger C
由于高危神经母细胞瘤（NB）预后差，需要新的治疗方式。因此，我们研究了NB细胞对γ-分泌酶抑制剂I（GSI-I）的敏感性。在NB细胞中，在体外和体内评估NOTCH信号传导活性、GSI-I的细胞效应及其细胞毒性机制。结果显示NOTCH信号传导与人NB细胞相关。在体外筛选的GSI中，GSI-I是NB细胞的最有效抑制剂。MYCN扩增和非扩增NB细胞均对GSI-I敏感。NB细胞中GSI-I的靶点是NOTCH和蛋白酶体。GSI-I引起G2/M期阻滞，MYCN的急性激活增强了这种阻滞，并导致有丝分裂功能障碍。GSI-I还诱导促凋亡NOXA。全身性GSI-I显著延长了携带MYCN非扩增原位患者来源的NB异种移植物的小鼠的存活时间，与有丝分裂灾难和血管生成减少相关，并且没有肠毒性的证据。总之，GSI-I对NB细胞中的多个靶点的活性和小鼠中胃肠道毒性的缺乏是有利的，值得进一步研究GSI-I在NB中的作用。
As high-risk neuroblastoma (NB) has a poor prognosis, new therapeutic modalities are needed. We therefore investigated the susceptibility of NB cells to γ-secretase inhibitor I (GSI-I). NOTCH signaling activity, the cellular effects of GSI-I and its mechanisms of cytotoxicity were evaluated in NB cells in vitro and in vivo. The results show that NOTCH signaling is relevant for human NB cells. Of the GSIs screened in vitro GSI-I was the most effective inhibitor of NB cells. Both MYCN-amplified and non-amplified NB cells were susceptible to GSI-I. Among the targets of GSI-I in NB cells were NOTCH and the proteasome. GSI-I caused G2/M arrest that was enhanced by acute activation of MYCN and led to mitotic dysfunction. GSI-I also induced proapoptotic NOXA. Survival of mice bearing an MYCN non-amplified orthotopic patient-derived NB xenograft was significantly prolonged by systemic GSI-I, associated with mitotic catastrophe and reduced angiogenesis, and without evidence of intestinal toxicity. In conclusion, the activity of GSI-I on multiple targets in NB cells and the lack of gastrointestinal toxicity in mice are advantageous and merit further investigations of GSI-I in NB.