Department of Otorhinolaryngology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
Department of Biochemistry and Molecular Biology, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, 400016, China.
J Biomed Sci. 2019 Feb 4;26(1):14. doi: 10.1186/s12929-019-0507-z.
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.
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.
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.
We show that NFBD1 depletion may possess sensitizing effects of PARP inhibitor, and consequently offers novel therapeutic options for a significant subset of patients.
鼻咽癌（NPC）是一种具有独特种族和地理分布的高度侵袭性肿瘤。由于晚期 NPC 有效联合化疗放疗的药物选择有限，因此迫切需要新的治疗方法。本研究旨在研究沉默 NFBD1 与 PARP 抑制联合作为 NPC 新的治疗策略的潜力。
为了研究 NFBD1 的功能，我们通过慢病毒介导的 shRNA 构建了 NFBD1 敲低的 NPC 细胞系，并通过集落形成、MTS 分析、彗星分析和凋亡分析来评估 NFBD1 敲低对 PARP 抑制的敏感性。通过 Western blot、免疫荧光和流式细胞术评估信号变化。此外，还使用异种移植模型来评估沉默 NFBD1 与 PARP 抑制联合的作用。
我们发现，沉默 NFBD1 与 PARP 抑制联合显著抑制细胞增殖和细胞周期检查点活性，增加细胞凋亡和 DNA 损伤。机制研究表明，NFBD1 缺失通过减少 BRCA1、BRCA2 和 RAD51 焦点的形成来阻断奥拉帕利诱导的同源重组修复。此外，在 NFBD1 缺陷的情况下，异种移植肿瘤模型显示对 PARP 抑制的敏感性显著增加。
我们表明 NFBD1 耗竭可能具有 PARP 抑制剂增敏作用，为相当一部分患者提供了新的治疗选择。
