Guo Zong-Pei, Hu Ying-Chun, Xie Yu, Jin Feng, Song Zhi-Quan, Liu Xiao-Dan, Ma Teng, Zhou Ping-Kun
Department of Radiation Toxicology and Oncology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, 100850, PR China.
Institute for Environmental Medicine and Radiation Hygiene, School of Public Health, University of South China, Hengyang, Hunan Province, 421001, PR China.
Biochem Biophys Res Commun. 2017 Jan 29;483(1):223-229. doi: 10.1016/j.bbrc.2016.12.162. Epub 2016 Dec 26.
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.
与泛素化一样，多项研究表明，NEDDylation参与双链断裂修复。BRCA1是同源重组修复中的关键修复因子之一，可能在NEDDylation下游发挥作用。BRCA1也是癌症中经常发生突变的基因，可作为PARP抑制剂的作用靶点。在此，我们使用NEDDylation抑制剂MLN4924进一步研究了NEDDylation与BRCA1复合物之间的相关性。MLN4924有效抑制BRCA1复合物成分募集至DNA损伤位点。因此，MLN4924可能与PARP抑制剂协同作用以抑制肿瘤。我们的结果表明，MLN4924与PARP抑制剂奥拉帕尼联合使用会损害非小细胞肺癌（NSCLC）细胞中的DNA修复过程。此外，MLN4924和奥拉帕尼显著抑制癌细胞生长。肺癌患者的Kaplan-Meier生存分析表明，NEDD8、BRCA1和PARP的高表达与较差的总生存期相关。因此，MLN4924与PARP抑制剂联合使用可能成为NSCLC治疗的新策略。
