Inhibition of Karyopherin beta 1 suppresses prostate cancer growth
Inhibition of Karyopherin beta 1 suppresses prostate cancer growth
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DOI：
10.1038/s41388-019-0745-2
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发表时间：
2019-06-13
期刊：
影响因子：
8
通讯作者：
Li, Xin
中科院分区：
文献类型：
--
作者：
Yang, Jian;Guo, Yuqi;Li, Xin
前列腺癌(Pca)的发生和发展需要多种致癌信号通路的激活。在细胞转化过程中，致癌因子的核质转运是由核仁蛋白介导的。然而，核转运蛋白在前列腺癌进展中的作用还没有很好的界定。在这里，我们报告了KPNB1，核仁组成蛋白β亚基的一个关键成员，在晚期前列腺癌中高度表达。进一步的研究表明，靶向KPNB1抑制了前列腺癌细胞的增殖。KPNB1基因的敲除减少了c-Myc的核转位、下游细胞周期调节器的表达以及染色质缩合调节因子1(RCC1)的磷酸化，RCC1是有丝分裂过程中纺锤体组装的关键蛋白。同时，芯片检测显示c-Myc与KPNB1启动子区域结合，提示c-Myc对KPNB1的表达具有正反馈调节作用。此外，KPNB1抑制可阻断NF-kappa B亚单位p50向细胞核的移位，导致PCa细胞凋亡率增加，肿瘤球体形成减少。此外，在C42B PCa细胞中稳定敲除KPNB1的皮下移植瘤模型验证了KPNB1的抑制可以在体内抑制前列腺癌的生长。此外，静脉注射KPNB1的特异性抑制剂Importazole，有效地减少了接种PC3 PCA细胞的小鼠的PCA肿瘤大小和重量。综上所述，我们的数据建立了KPNB1与前列腺癌易感的c-Myc、核因子-kB和细胞周期调节因子之间的功能联系。更重要的是，抑制KPNB1可能成为治疗前列腺癌的新靶点。
Prostate cancer (PCa) initiation and progression requires activation of numerous oncogenic signaling pathways. Nuclear-cytoplasmic transport of oncogenic factors is mediated by Karyopherin proteins during cell transformation. However, the role of nuclear transporter proteins in PCa progression has not been well defined. Here, we report that the KPNB1, a key member of Karyopherin beta subunits, is highly expressed in advanced prostate cancers. Further study showed that targeting KPNB1 suppressed the proliferation of prostate cancer cells. The knockdown of KPNB1 reduced nuclear translocation of c-Myc, the expression of downstream cell cycle modulators, and phosphorylation of regulator of chromatin condensation 1 (RCC1), a key protein for spindle assembly during mitosis. Meanwhile, CHIP assay demonstrated the binding of c-Myc to KPNB1 promoter region, which indicated a positive feedback regulation of KPNB1 expression mediated by the c-Myc. In addition, NF-kappa B subunit p50 translocation to nuclei was blocked by KPNB1 inhibition, which led to an increase in apoptosis and a decrease in tumor sphere formation of PCa cells. Furthermore, subcutaneous xenograft tumor models with a stable knockdown of KPNB1 in C42B PCa cells validated that the inhibition of KPNB1 could suppress the growth of prostate tumor in vivo. Moreover, the intravenously administration of importazole, a specific inhibitor for KPNB1, effectively reduced PCa tumor size and weight in mice inoculated with PC3 PCa cells. In summary, our data established the functional link between KPNB1 and PCa prone c-Myc, NF-kB, and cell cycle modulators. More importantly, inhibition of KPNB1 could be a new therapeutic target for PCa treatment.