Ribosomal Biogenesis and Translational Flux Inhibition by the Selective Inhibitor of Nuclear Export (SINE) XPO1 Antagonist KPT-185.
Ribosomal Biogenesis and Translational Flux Inhibition by the Selective Inhibitor of Nuclear Export (SINE) XPO1 Antagonist KPT-185.
复制标题
核体生物发生和核输出选择性抑制剂（SINE）XPO1拮抗剂KPT-185的抑制作用。
DOI：
10.1371/journal.pone.0137210
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Andreeff M
中科院分区：
文献类型：
--
作者：
Tabe Y;Kojima K;Yamamoto S;Sekihara K;Matsushita H;Davis RE;Wang Z;Ma W;Ishizawa J;Kazuno S;Kauffman M;Shacham S;Fujimura T;Ueno T;Miida T;Andreeff M
套细胞淋巴瘤（MCL）是一种侵袭性B细胞淋巴瘤，其特征是几种生长调节致癌效应物的异常表达。输出蛋白1（XPO 1）介导许多分子的核质转运，包括致癌生长调节因子、RNA和核糖体亚基。在MCL细胞中，小分子KPT-185阻断XPO 1功能并发挥抗增殖作用。在这项研究中，我们研究了这种假定的抗肿瘤作用的分子机制MCL细胞使用细胞生长/活力测定，免疫印迹，基因表达分析，和绝对定量蛋白质组学。KPT-185通过抑制致癌介质（例如，XPO 1、细胞周期蛋白D1、c-Myc、PIM 1和Bcl-2家族成员）、核糖体生物发生的抑制和翻译/伴侣蛋白（例如，PIM 2、EEF 1A 1、EEF 2和HSP 70），它们是由热休克因子1调节的翻译/转录网络的一部分。这些结果阐明了一种新的机制，其中核糖体生物合成似乎是XPO 1促进肿瘤细胞存活的关键组成部分。因此，我们认为阻断XPO 1可能是治疗MCL和其他过表达XPO 1的恶性肿瘤的一种有前途的新策略。
Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma characterized by the aberrant expression of several growth-regulating, oncogenic effectors. Exportin 1 (XPO1) mediates the nucleocytoplasmic transport of numerous molecules including oncogenic growth-regulating factors, RNAs, and ribosomal subunits. In MCL cells, the small molecule KPT-185 blocks XPO1 function and exerts anti-proliferative effects. In this study, we investigated the molecular mechanisms of this putative anti-tumor effect on MCL cells using cell growth/viability assays, immunoblotting, gene expression analysis, and absolute quantification proteomics. KPT-185 exhibited a p53-independent anti-lymphoma effect on MCL cells, by suppression of oncogenic mediators (e.g., XPO1, cyclin D1, c-Myc, PIM1, and Bcl-2 family members), repression of ribosomal biogenesis, and downregulation of translation/chaperone proteins (e.g., PIM2, EEF1A1, EEF2, and HSP70) that are part of the translational/transcriptional network regulated by heat shock factor 1. These results elucidate a novel mechanism in which ribosomal biogenesis appears to be a key component through which XPO1 contributes to tumor cell survival. Thus, we propose that the blockade of XPO1 could be a promising, novel strategy for the treatment of MCL and other malignancies overexpressing XPO1.