MLN4924 suppresses the BRCA1 complex and synergizes with PARP inhibition in NSCLC cells

Autor: Yu Xie, Teng Ma, Ping-Kun Zhou, Feng Jin, Hu Yingchun, Zong-Pei Guo, Zhi-Quan Song, Xiao-Dan Liu
Rok vydání: 2016
Předmět:
0301 basic medicine
Lung Neoplasms
NEDD8 Protein
DNA repair
DNA damage
Poly ADP ribose polymerase
Ubiquitin-Protein Ligases
Biophysics
Poly (ADP-Ribose) Polymerase-1
Cyclopentanes
Kaplan-Meier Estimate
Biology
Poly(ADP-ribose) Polymerase Inhibitors
Biochemistry
NEDD8
Piperazines
Olaparib
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Carcinoma
Non-Small-Cell Lung
Cell Line
Tumor
Antineoplastic Combined Chemotherapy Protocols
Humans
Histone Chaperones
Molecular Biology
Ubiquitins
BRCA1 Protein
Tumor Suppressor Proteins
Nuclear Proteins
Cell Biology
DNA-Binding Proteins
030104 developmental biology
Pyrimidines
chemistry
030220 oncology & carcinogenesis
Multiprotein Complexes
PARP inhibitor
Cancer cell
Cancer research
Phthalazines
Neddylation
Carrier Proteins
DNA Damage
Zdroj: Biochemical and biophysical research communications. 483(1)
ISSN: 1090-2104
Popis: 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.
Databáze: OpenAIRE
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