Nuclear Transport Receptor Importin-β Inhibition Enhances Cell Cycle Arrest Induced by CKS2 Knockdown to Suppress Neuroblastoma Progression

IF 3.8 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Shouhua Zhang, Xiaozhen Meng, Deng Xiang, Hui Huang, Yangfan Ge, Yishan Zhan, Kehao Li, Xiaoyun Tan
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Abstract

Cyclin-dependent kinases regulatory subunit 2 (CKS2) is a key regulator of the cell cycle, but its role in neuroblastoma remains poorly understood. This study investigates the function and mechanisms of CKS2 in neuroblastoma through bioinformatics analyses, as well as in vitro and in vivo experiments. Data from the GEO and TCGA databases indicate that elevated CKS2 expression is associated with poor prognosis in neuroblastoma. Analysis of clinical tumor samples and cell lines further confirmed that CKS2 was significantly overexpressed, particularly in high-risk neuroblastoma patient-derived tissues. Functional studies revealed that CKS2 knockdown reduced cell proliferation and invasion, induced apoptosis, and caused cell cycle arrest in neuroblastoma cells. In vivo, tumors formed from CKS2-silenced cells showed markedly reduced growth. Mechanistically, CKS2 knockdown decreased the phosphorylation of CDK1 (Thr161) and Cyclin B1 (Ser126), suggesting impaired cell division signaling. Treatment with importazole, an importin-β inhibitor, caused CKS2 to accumulate in the cytoplasm rather than in the nucleus, inhibiting proliferation and increasing apoptosis of neuroblastoma cells. Notably, the combination of CKS2 knockdown and importazole treatment produced a stronger anti-tumor effect than either intervention alone. These findings demonstrate that CKS2 promotes neuroblastoma progression by facilitating cell division via the CDK1/Cyclin B1 complex. Targeting CKS2, especially in combination with nuclear import inhibition, offers a promising therapeutic strategy for neuroblastoma.

核转运受体输入蛋白-β抑制增强CKS2敲低诱导的细胞周期阻滞抑制神经母细胞瘤进展
细胞周期蛋白依赖性激酶调控亚单位2 (CKS2)是细胞周期的关键调节因子,但其在神经母细胞瘤中的作用尚不清楚。本研究通过生物信息学分析和体内外实验,探讨CKS2在神经母细胞瘤中的功能和机制。来自GEO和TCGA数据库的数据表明,CKS2表达升高与神经母细胞瘤的不良预后相关。对临床肿瘤样本和细胞系的分析进一步证实,CKS2显著过表达,特别是在高危神经母细胞瘤患者来源的组织中。功能研究显示,CKS2敲低可降低神经母细胞瘤细胞的增殖和侵袭,诱导细胞凋亡,并导致细胞周期阻滞。在体内,由cks2沉默细胞形成的肿瘤生长明显降低。机制上,CKS2敲低降低了CDK1 (Thr161)和Cyclin B1 (Ser126)的磷酸化,表明细胞分裂信号受损。importazole(一种进口蛋白β抑制剂)可导致CKS2在细胞质中而非细胞核中积累,从而抑制神经母细胞瘤细胞的增殖并增加细胞凋亡。值得注意的是,CKS2敲除与importazole联合治疗比单独干预具有更强的抗肿瘤作用。这些发现表明,CKS2通过CDK1/Cyclin B1复合物促进细胞分裂,从而促进神经母细胞瘤的进展。靶向CKS2,特别是联合核输入抑制,为神经母细胞瘤的治疗提供了一种很有前景的治疗策略。
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来源期刊
Neurochemical Research
Neurochemical Research 医学-神经科学
CiteScore
7.70
自引率
2.30%
发文量
320
审稿时长
6 months
期刊介绍: Neurochemical Research is devoted to the rapid publication of studies that use neurochemical methodology in research on nervous system structure and function. The journal publishes original reports of experimental and clinical research results, perceptive reviews of significant problem areas in the neurosciences, brief comments of a methodological or interpretive nature, and research summaries conducted by leading scientists whose works are not readily available in English.
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