2. Academic Validation
  3. 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

  • Biochem Biophys Res Commun. 2017 Jan 29;483(1):223-229. doi: 10.1016/j.bbrc.2016.12.162.
Zong-Pei Guo 1,  Ying-Chun Hu 1,  Yu Xie 2,  Feng Jin 3,  Zhi-Quan Song 1,  Xiao-Dan Liu 1,  Teng Ma 4,  Ping-Kun Zhou 5
Affiliations

Affiliations

  • 1 Department of Radiation Toxicology and Oncology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, 100850, PR China.
  • 2 Institute for Environmental Medicine and Radiation Hygiene, School of Public Health, University of South China, Hengyang, Hunan Province, 421001, PR China.
  • 3 Xiangya School of Public Health, Central South University, Changsha, Hunan Province, 410078, PR China.
  • 4 Department of Radiation Toxicology and Oncology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, 100850, PR China. Electronic address: mateng82913@163.com.
  • 5 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. Electronic address: zhoupk@bmi.ac.cn.
PMID: 28034751 DOI: 10.1016/j.bbrc.2016.12.162
Abstract

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.

Keywords

BRCA1; Double strand break; NSCLC; Neddylation; PARP1.

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