MLN4924 suppresses the BRCA1 complex and synergizes with PARP inhibition in NSCLC cells
MLN4924 suppresses the BRCA1 complex and synergizes with PARP inhibition in NSCLC cells
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MLN4924 抑制 BRCA1 复合物并与 NSCLC 细胞中的 PARP 抑制协同作用
DOI：
10.1016/j.bbrc.2016.12.162
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发表时间：
2017-01-29
影响因子：
3.1
通讯作者：
Zhou, Ping-Kun
中科院分区：
文献类型：
--
作者：
Guo, Zong-pei;Hu, Ying-Chun;Zhou, Ping-Kun
像泛素化一样，一些研究已经证明neddylation参与了双链断裂修复。BRCA 1是同源重组修复中的关键修复因子之一，可能在neddylation的下游发挥作用。BRCA 1也是癌症中经常突变的基因，可作为PARP抑制剂的靶点。在此，我们使用neddylation抑制剂MLN 4924进一步研究了neddylation和BRCA 1复合物之间的相关性。MLN 4924有效抑制BRCA 1复合物组分向DNA损伤位点的募集。因此，MLN 4924可能与PARP抑制剂协同抑制肿瘤。我们的研究结果表明，MLN 4924和PARP抑制剂奥拉帕尼联合给药会损害NSCLC细胞的DNA修复过程。此外，MLN 4924和奥拉帕尼显著抑制癌细胞生长。肺癌患者的Kaplan-Meier生存分析显示，NEDD 8、BRCA 1和PARP的高表达与较差的总生存相关。因此，MLN 4924和PARP抑制剂联合用药可作为NSCLC治疗的新策略。(C)2016 Elsevier Inc. All rights reserved.
Like ubiquitination, several studies have demonstrated that neddylation is implicated to be involved in the double strand break repair. BRCA1 is one of the key repair factors in the homologous recombination repair and may play a downstream role of the neddylation. BRCA1 is also a frequently mutated gene in cancers, which serve as the targets for PARP inhibitors. Here we further investigated the correlation between neddylation and BRCA1 complex using neddylation inhibitor MLN4924. MLN4924 efficiently inhibited the recruitment of components of BRCA1 complex to DNA damage sites. Thus MLN4924 may collaborate with PARP inhibitor to suppress tumor. Our results showed that combination MLN4924 and PARP inhibitor Olaparib impaired the DNA repair process in NSCLC cells. Furthermore, MLN4924 and Olaparib significantly inhibited the cancer cell growth. Kaplan-Meier survival analysis from lung cancer patients showed that high expression of NEDD8, BRCA1 and PARPs correlate with worse overall survival. Thus the combination of MLN4924 and PARP inhibitor may serve as a new strategy for NSCLC treatment. (C) 2016 Elsevier Inc. All rights reserved.