CDK4的自噬降解是NVP-BEZ235处理的神经母细胞瘤G0/G1细胞周期停滞的原因。

IF 5.4 3区材料科学 Q2 CHEMISTRY, PHYSICAL ACS Applied Energy Materials Pub Date : 2024-12-31 Epub Date: 2024-08-01 DOI:10.1080/15384047.2024.2385517

Zhen Liu, Xiao-Yang Wang, Han-Wei Wang, Shan-Ling Liu, Chao Zhang, Feng Liu, Ying Guo, Feng-Hou Gao

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引用次数: 0

摘要

背景：CDK4高度表达，与晚期神经母细胞瘤（NB）的预后不良和存活率降低有关。与传统的CDK4抑制剂相比，靶向CDK4降解是一种具有潜在前景的治疗策略。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被提及：结果：我们发现自噬是降解 CDK4 的新途径。首先，CDK4的自噬降解对于NVP-BEZ235诱导的G0/G1停滞至关重要，CDK4的过表达、自噬抑制以及自噬相关基因的阻断都证明了这一点。其次，我们首次证明了在NVP-BEZ235处理的NB细胞中，p62与CDK4结合，然后进入自噬-溶酶体，以CTSB依赖的方式降解CDK4。在NVP-BEZ235处理的NB异种移植小鼠模型中也观察到了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细胞周期停滞中起着关键作用。

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Autophagic degradation of CDK4 is responsible for G0/G1 cell cycle arrest in NVP-BEZ235-treated neuroblastoma.

Background: 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.

Results: 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.

Conclusions: Autophagic degradation of CDK4 plays a pivotal role in G0/G1 cell cycle arrest in NB cells treated with NVP-BEZ235.

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来源期刊

ACS Applied Energy Materials Materials Science-Materials Chemistry

CiteScore

10.30

自引率

6.20%

发文量

1368

期刊介绍： ACS Applied Energy Materials is an interdisciplinary journal publishing original research covering all aspects of materials, engineering, chemistry, physics and biology relevant to energy conversion and storage. The journal is devoted to reports of new and original experimental and theoretical research of an applied nature that integrate knowledge in the areas of materials, engineering, physics, bioscience, and chemistry into important energy applications.