Liu Zhen, Wang Xiao-Yang, Wang Han-Wei, Liu Shan-Ling, Zhang Chao, Liu Feng, Guo Ying, Gao Feng-Hou
Department of Clinical Laboratory, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China.
Department of Oncology, Shanghai ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Cancer Biol Ther. 2024 Dec 31;25(1):2385517. doi: 10.1080/15384047.2024.2385517. Epub 2024 Aug 1.
CDK4 is highly expressed and associated with poor prognosis and decreased survival in advanced neuroblastoma (NB). Targeting CDK4 degradation presents a potentially promising therapeutic strategy compared to conventional CDK4 inhibitors. However, the autophagic degradation of the CDK4 protein and its anti-proliferation effect in NB cells has not been mentioned.
We identified autophagy as a new pathway for the degradation of CDK4. Firstly, autophagic degradation of CDK4 is critical for NVP-BEZ235-induced G0/G1 arrest, as demonstrated by the overexpression of CDK4, autophagy inhibition, and blockade of autophagy-related genes. Secondly, we present the first evidence that p62 binds to CDK4 and then enters the autophagy-lysosome to degrade CDK4 in a CTSB-dependent manner in NVP-BEZ235 treated NB cells. Similar results regarding the interaction between p62 and CDK4 were observed in the NVP-BEZ235 treated NB xenograft mouse model.
Autophagic degradation of CDK4 plays a pivotal role in G0/G1 cell cycle arrest in NB cells treated with NVP-BEZ235.
细胞周期蛋白依赖性激酶4（CDK4）在晚期神经母细胞瘤（NB）中高表达，与预后不良和生存率降低相关。与传统的CDK4抑制剂相比，靶向CDK4降解是一种潜在的有前景的治疗策略。然而，CDK4蛋白的自噬降解及其在NB细胞中的抗增殖作用尚未见报道。
我们确定自噬是CDK4降解的新途径。首先，CDK4的自噬降解对于NVP-BEZ235诱导的G0/G1期阻滞至关重要，这通过CDK4过表达、自噬抑制和自噬相关基因的阻断得以证明。其次，我们首次证明在NVP-BEZ235处理的NB细胞中，p62与CDK4结合，然后以依赖组织蛋白酶B（CTSB）的方式进入自噬溶酶体降解CDK4。在NVP-BEZ235处理的NB异种移植小鼠模型中观察到了关于p62与CDK4相互作用的类似结果。
CDK4的自噬降解在NVP-BEZ235处理的NB细胞的G0/G1细胞周期阻滞中起关键作用。
