- 作者: Zhihai Wang, Wenqi Zuo, Quan Zeng, Yi Qian, Yanshi Li, Chuan Liu, Jue Wang, Shixun Zhong, Youquan Bu and Guohua Hu
- 作者服務機構: Department of Otorhinolaryngology, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
- 中文摘要:
- 英文摘要:
Background
Nasopharyngeal carcinoma (NPC), a highly invasive tumor, exhibits a distinctive racial and geographic distribution. As options of agents for effective combination chemoradiotherapy for advanced NPC are limited, novel therapeutic approaches are desperately needed. Here the potential of silencing NFBD1 in combination with PARP inhibition as a novel therapeutic strategy for NPC was investigated.
Methods
To investigate the function of NFBD1, we created NFBD1-depleted NPC cell lines via lentivirus mediated shRNA, and the colony formation, MTS assay, comet assay and apoptosis analysis were used to evaluate the sensitivity of NFBD1 knockdown on PARP inhibition. The signaling change was assessed by western blot, Immunofluorescence and flow cytometry. Furthermore, Xenografts model was used to evaluate the role of silencing NFBD1 in combination with PARP inhibition.
Results
We find that silencing NFBD1 in combination with PARP inhibition significantly inhibits the cell proliferation and cell cycle checkpoint activity, and increases the apoptosis and DNA damage. Mechanistic studies reveal that NFBD1 loss blocks olaparib-induced homologous recombination repair by decreasing the formation of BRCA1, BRCA2 and RAD51 foci. Furthermore, the xenograft tumor model demonstrated significantly increases sensitivity towards PARP inhibition under NFBD1 deficiency.
Conclusions
We show that NFBD1 depletion may possess sensitizing effects of PARP inhibitor, and consequently offers novel therapeutic options for a significant subset of patients. - 中文關鍵字:
- 英文關鍵字: Nasopharyngeal carcinoma, PARP inhibitor; homologous recombination, NFBD1/MDC1, DNA damage response