title: MLN4924 suppresses the BRCA1 complex and synergizes with PARP inhibition in NSCLC cells.
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.
authors.affiliation: Department of Radiation Toxicology and Oncology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, 100850, PR China.
authors.forename: Zong-Pei
authors.initials: ZP
authors.lastname: Guo
authors.affiliation: Department of Radiation Toxicology and Oncology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, 100850, PR China.
authors.forename: Ying-Chun
authors.initials: YC
authors.lastname: Hu
authors.affiliation: Institute for Environmental Medicine and Radiation Hygiene, School of Public Health, University of South China, Hengyang, Hunan Province, 421001, PR China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Xiangya School of Public Health, Central South University, Changsha, Hunan Province, 410078, PR China.
authors.forename: Feng
authors.initials: F
authors.lastname: Jin
authors.affiliation: Department of Radiation Toxicology and Oncology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, 100850, PR China.
authors.forename: Zhi-Quan
authors.initials: ZQ
authors.lastname: Song
authors.affiliation: Department of Radiation Toxicology and Oncology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, 100850, PR China.
authors.forename: Xiao-Dan
authors.initials: XD
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Teng
authors.initials: T
authors.lastname: Ma
authors.affiliation: 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.
authors.forename: Ping-Kun
authors.initials: PK
authors.lastname: Zhou
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D019313:BRCA1 Protein; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D003517:Cyclopentanes / Q000008:administration & dosage / Q000494:pharmacology*; D004249:DNA Damage / Q000187:drug effects; D004268:DNA-Binding Proteins; D056488:Histone Chaperones; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D046912:Multiprotein Complexes; D000075687:NEDD8 Protein; D009687:Nuclear Proteins / Q000378:metabolism; D010793:Phthalazines / Q000008:administration & dosage / Q000494:pharmacology; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D014452:Ubiquitins / Q000378:metabolism
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D002352:Carrier Proteins; D003517:Cyclopentanes; D004268:DNA-Binding Proteins; D056488:Histone Chaperones; D046912:Multiprotein Complexes; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; D009687:Nuclear Proteins; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011743:Pyrimidines; D025521:Tumor Suppressor Proteins; C466234:UIMC1 protein, human; D014452:Ubiquitins; C102449:BARD1 protein, human; D044767:Ubiquitin-Protein Ligases; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; C539933:pevonedistat; C531550:olaparib
keywords: BRCA1; Double strand break; NSCLC; Neddylation; PARP1