Ando Kiyohiro, Cázares-Ordoñez Verna, Makishima Makoto, Yokoyama Atsushi, Suenaga Yusuke, Nagase Hiroki, Kobayashi Shinichi, Kamijo Takehiko, Koshinaga Tsugumichi, Wada Satoshi
Department of Clinical Diagnostic Oncology, Showa University Clinical Research Institute for Clinical Pharmacology and Therapeutics, 6-11-11 Kita-Karasuyama, Setagaya-ku, Tokyo 157-8577, Japan.
Research Institute for Clinical Oncology, Saitama Cancer Center, 818 Komuro, Ina, Saitama, Japan.
J Oncol. 2020 Sep 15;2020:2752417. doi: 10.1155/2020/2752417. eCollection 2020.
Checkpoint kinase 1 (CHK1) plays a key role in genome surveillance and integrity throughout the cell cycle. Selective inhibitors of CHK1 (CHK1i) are undergoing clinical evaluation for various human malignancies, including neuroblastoma. Recently, we reported that CHK1i, PF-477736, induced a p53-mediated DNA damage response. As a result, the cancer cells were able to repair DNA damage and became less sensitive to CHK1i. In this study, we discovered that PF-477736 increased expression of MDM2 oncogene along with CHK1i-induced replication defects in neuroblastoma NB-39-nu cells. A mass spectrometry analysis of protein binding to MDM2 in the presence of CHK1i identified the centrosome-associated family protein 131 (CEP131), which was correlated with unfavorable prognosis of neuroblastoma patients. We revealed that MDM2 was associated with CEP131 protein degradation, whereas overexpression of CEP131 accelerated neuroblastoma cell growth and exhibited resistance to CHK1i-induced replication defects. Thus, these findings may provide a future therapeutic strategy against centrosome-associated oncogenes involving CEP131 as a target in neuroblastoma.
关卡激酶1（CHK1）在整个细胞周期的基因组监测和完整性方面发挥着关键作用。CHK1的选择性抑制剂（CHK1i）正在针对包括神经母细胞瘤在内的各种人类恶性肿瘤进行临床评估。最近，我们报道了CHK1i（PF - 477736）诱导了p53介导的DNA损伤反应。结果，癌细胞能够修复DNA损伤并对CHK1i变得不那么敏感。在这项研究中，我们发现PF - 477736在神经母细胞瘤NB - 39 - nu细胞中与CHK1i诱导的复制缺陷一起增加了MDM2癌基因的表达。在存在CHK1i的情况下对与MDM2结合的蛋白质进行质谱分析，鉴定出了中心体相关家族蛋白131（CEP131），其与神经母细胞瘤患者的不良预后相关。我们发现MDM2与CEP131蛋白降解有关，而CEP131的过表达加速了神经母细胞瘤细胞的生长，并表现出对CHK1i诱导的复制缺陷的抗性。因此，这些发现可能为针对以CEP131为靶点的涉及中心体相关癌基因的神经母细胞瘤提供一种未来的治疗策略。
