Synergistic effect of Nutlin-3 combined with MG-132 on schwannoma cells through restoration of merlin and p53 tumour suppressors.
Synergistic effect of Nutlin-3 combined with MG-132 on schwannoma cells through restoration of merlin and p53 tumour suppressors.
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Nutlin-3联合MG-132通过恢复merlin和p53肿瘤抑制因子对神经鞘瘤细胞产生协同作用
DOI：
10.1016/j.ebiom.2018.09.042
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发表时间：
2018-10
期刊：
影响因子：
11.1
通讯作者：
Wu H
中科院分区：
文献类型：
--
作者：
Chen H;Xue L;Huang H;Wang H;Zhang X;Zhu W;Wang Z;Wang Z;Wu H
绝大多数零星的前庭schwannomas（VSS）是由于编码Merlin的NF2基因的突变。零星的VSS表现出可变的生长模式，只有一小部分肿瘤是快速生长的。但是，基本机制仍然不确定。
DNA测序和剂量分析用于鉴定零星schwannomas中的NF2突变状态。通过免疫印迹，QRT-PCR和免疫荧光评估了Merlin和p53-MDM2的表达和细胞局部定位。进行了体外和体内研究，以揭示Nutlin-3（MDM2抑制剂）和/或MG-132（蛋白酶体抑制剂）对Schwannomas的影响。通过CCK-8测定，EDU染色和流式细胞仪分析评估切旺人细胞的增殖。
NF2的双重遗传命中倾向于在快速增长的肿瘤中发生，其特征是缺乏Merlin。证明了p53-MDM2的放松管制可介导梅林缺陷型肿瘤的生长，其特征是稳定的MDM2的核积累，导致核导出p53降解。 Nutlin-3通过Merlin和p53的合作恢复，阻止了切旺纳马瘤细胞的增殖，并伴随着两种蛋白质从细胞质到细胞核的穿梭。我们进一步证明了具有和没有Merlin表达的Schwannoma细胞之间对Nutlin-3的敏感性差异。 Nutlin-3与MG-132结合使用了该组间差异，并通过p53的协调重新激活而触发了对雪旺纳马瘤生长的较强抑制作用。
这些发现呈现针对零星schwannomas发病机理的治疗策略。
中国国家自然科学基金会。
The great majority of sporadic vestibular schwannomas (VSs) are due to the mutations of the NF2 gene encoding merlin. Sporadic VSs exhibit variable growth patterns and only a small fraction of the tumours are fast-growing; however, the underlying mechanisms remain undefined. DNA sequencing and dosage analysis were used to identify the NF2 mutation status in sporadic schwannomas. The expression and sub-cellular localization of merlin and p53-MDM2 were assessed by immunoblotting, qRT-PCR and immunofluorescence. In vitro and in vivo studies were performed to reveal the effects of Nutlin-3 (a MDM2 inhibitor) and/or MG-132(a proteasome inhibitor) on schwannomas. The proliferation of schwannoma cells was assessed by CCK-8 assay, EdU staining and Flow cytometry analysis. Double genetic hits of NF2 tended to occur in fast-growing tumours, characterized by the absence of merlin. The deregulation of p53-MDM2 was demonstrated to mediate merlin-deficient tumour growth, characterized by a nuclear accumulation of stabilized MDM2, contributing to a nuclear export of p53 for degradation. Nutlin-3 blocked the proliferation of schwannoma cells via a cooperative recovery of merlin and p53, accompanied by the shuttling of both proteins from the cytoplasm to the nucleus. We further demonstrated a difference in the sensitivity to Nutlin-3 between schwannoma cells with and without merlin expression. Nutlin-3 combined with MG-132 narrowed this between-group difference and triggered stronger inhibitory effects on the growth of schwannomas through coordinated reactivation of p53. These findings present treatment strategies directed on the pathogenesis of sporadic schwannomas. National Natural Science Foundation of China.
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影响因子：
11.1
作者：
Harhouri K;Navarro C;Depetris D;Mattei MG;Nissan X;Cau P;De Sandre-Giovannoli A;Lévy N
通讯作者：
Lévy N
影响因子：
3.9
作者：
Chang, ZeNan;Guo, Chin-Lin;Ahronowitz, Iris;Stemmer-Rachamimov, Anat O.;MacCollin, Mia;Nunes, Fabio P.
通讯作者：
Nunes, Fabio P.
影响因子：
64.5
作者：
Li W;You L;Cooper J;Schiavon G;Pepe-Caprio A;Zhou L;Ishii R;Giovannini M;Hanemann CO;Long SB;Erdjument-Bromage H;Zhou P;Tempst P;Giancotti FG
通讯作者：
Giancotti FG
影响因子：
10.5
作者：
Inoue, K;Zindy, F;Sherr, CJ
通讯作者：
Sherr, CJ
影响因子：
30.8
作者：
Agnihotri, Sameer;Jalali, Shahrzad;Zadeh, Gelareh
通讯作者：
Zadeh, Gelareh