Department of Pediatrics, Division of Hematology-Oncology, University of California San Diego, La Jolla, CA 92093, USA.
Peckham Center for Cancer and Blood Disorders, Rady Children's Hospital, San Diego, CA 92123, USA.
Int J Mol Sci. 2023 Sep 7;24(18):13780. doi: 10.3390/ijms241813780.
Neuroblastoma (NB) is a pediatric malignancy originating from neural crest cells of the sympathetic nervous system that accounts for 15% of all pediatric cancer deaths. Despite advances in treatment, high-risk NB remains difficult to cure, highlighting the need for novel therapeutic approaches. Ubiquitin-specific protease 7 (USP7) is a deubiquitinase that plays a critical role in tumor suppression and DNA repair, and overexpression has been associated with tumor aggressiveness in a variety of tumors, including NB. Therefore, USP7 is a potential therapeutic target for NB. The tumor suppressor p53 is a known target of USP7, and therefore reactivation of the p53 pathway may be an effective therapeutic strategy for NB treatment. We hypothesized that inhibition of USP7 would be effective against NB tumor growth. Using a novel USP7 inhibitor, Almac4, we have demonstrated significant antitumor activity, with significant decreases in both cell proliferation and cell viability in wild-type NB cell lines. USP7 inhibition in NB cells activated the p53 pathway via USP7 and MDM2 degradation, leading to reduced p53 ubiquitination and increased p53 expression in all sensitive NB cells. In addition, USP7 inhibition led to decreased N-myc protein levels in both -amplified and -nonamplified NB cell lines, but no correlation was observed between amplification and treatment response. USP7 inhibition induced apoptosis in all wild-type NB cell lines. USP7 inhibition also induced EZH2 ubiquitination and degradation. Lastly, the combination of USP7 and MDM2 inhibition showed enhanced efficacy. Our data suggests that USP7 inhibition may be a promising therapeutic strategy for children with high-risk and relapsed NB.
神经母细胞瘤（NB）是一种起源于交感神经系统神经嵴细胞的儿科恶性肿瘤，占所有儿科癌症死亡人数的 15%。尽管治疗取得了进展，但高危 NB 仍然难以治愈，这凸显了需要新的治疗方法。泛素特异性蛋白酶 7（USP7）是一种去泛素化酶，在肿瘤抑制和 DNA 修复中发挥着关键作用，其过度表达与多种肿瘤的肿瘤侵袭性有关，包括 NB。因此，USP7 是 NB 的一个潜在治疗靶点。肿瘤抑制因子 p53 是 USP7 的已知靶点，因此重新激活 p53 途径可能是 NB 治疗的有效治疗策略。我们假设抑制 USP7 将对 NB 肿瘤生长有效。使用一种新型的 USP7 抑制剂 Almac4，我们已经证明了其具有显著的抗肿瘤活性，在野生型 NB 细胞系中，细胞增殖和细胞活力均显著降低。USP7 抑制在 NB 细胞中通过 USP7 和 MDM2 降解激活了 p53 途径，导致 p53 泛素化减少和所有敏感 NB 细胞中的 p53 表达增加。此外，USP7 抑制导致两种 -扩增和 -非扩增 NB 细胞系中的 N-myc 蛋白水平降低，但在 -扩增和治疗反应之间没有观察到相关性。USP7 抑制诱导所有野生型 NB 细胞系的细胞凋亡。USP7 抑制也诱导了 EZH2 的泛素化和降解。最后，USP7 和 MDM2 抑制的联合使用显示出增强的疗效。我们的数据表明，USP7 抑制可能是治疗高危和复发性 NB 儿童的一种有前途的治疗策略。
