Cyclin-Dependent Kinase 5 Decreases in Gastric Cancer and Its Nuclear Accumulation Suppresses Gastric Tumorigenesis
Cyclin-Dependent Kinase 5 Decreases in Gastric Cancer and Its Nuclear Accumulation Suppresses Gastric Tumorigenesis
复制标题
胃癌中细胞周期蛋白依赖性激酶 5 的减少及其核积聚抑制胃肿瘤的发生
DOI：
10.1158/1078-0432.ccr-14-1950
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发表时间：
2015-03-15
影响因子：
11.5
通讯作者：
Zhang, Jie
中科院分区：
文献类型：
--
作者：
Cao, Longlong;Zhou, Jiechao;Zhang, Jie
目的：作为一种非细胞周期蛋白依赖性的非典型CDK，CDK5在胃癌细胞增殖调控中的作用尚不清楚。实验设计：采用Western blotting、免疫组织化学和实时定量聚合酶链式反应技术检测437例胃癌组织和癌旁组织中CDK5的表达。检测CDK5在胃癌细胞增殖过程中的亚细胞转位。探讨核CDK5在胃癌发生、增殖和体外异种移植中的作用。此外，通过在PubChem数据库中筛选破坏CDK5与其核出口促进剂关联的化合物，我们确定了一个抑制胃癌细胞生长的小分子(NS-0011)。结果：CDK5在大多数胃癌组织中显著降低，且CDK5的降低与胃癌的严重程度、淋巴结转移和患者的5年病死率相关。CDK5在肿瘤组织和胃癌细胞系中的核定位显著降低，而核靶向CDK5的外源表达抑制了胃癌细胞的增殖和异种移植。小分子NS-0011增加了CDK5在细胞核中的积聚，抑制了癌细胞的增殖和异种移植瘤的形成。结论：CDK5的低表达与胃癌患者的总体生存不良有关，CDK5的核积聚抑制了人胃癌细胞的增殖和致瘤性。临床癌症资源；21(6)；1419-28。©2015年AACR。
Purpose: As a cyclin-independent atypical CDK, the role of CDK5 in regulating cell proliferation in gastric cancer remains unknown. Experimental Design: Expression of CDK5 in gastric tumor and paired adjacent noncancerous tissues from 437 patients was measured by Western blotting, immunohistochemistry, and real-time PCR. The subcellular translocation of CDK5 was monitored during gastric cancer cell proliferation. The role of nuclear CDK5 in gastric cancer tumorigenic proliferation and ex vivo xenografts was explored. Furthermore, by screening for compounds in the PubChem database that disrupt CDK5 association with its nuclear export facilitator, we identified a small molecular (NS-0011) that inhibits gastric cancer cell growth. Results: CDK5 level was significantly decreased in the majority of gastric tumor tissues, and the reduction of CDK5 correlated with the severity of gastric cancer based on tumor and lymph node metastasis and patient 5-year fatality rate. Nuclear localization of CDK5 was found to be significantly decreased in tumor tissues and gastric cancer cell lines, whereas exogenously expression of nucleus-targeted CDK5 inhibited the proliferation and xenograft implantation of gastric cancer cells. Treatment with the small molecule NS-0011, which increases CDK5 accumulation in the nucleus, suppressed both cancer cell proliferation and xenograft tumorigenesis. Conclusions: Our results suggest that low CDK5 expression is associated with poor overall survival in patients with gastric cancer, and nuclear accumulation of CDK5 inhibits the proliferation and tumorigenicity of human gastric cancer cells. Clin Cancer Res; 21(6); 1419–28. ©2015 AACR.