CCL5 promotes proliferation of MCF-7 cells through mTOR-dependent mRNA translation
CCL5 promotes proliferation of MCF-7 cells through mTOR-dependent mRNA translation
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DOI：
10.1016/j.bbrc.2009.07.035
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发表时间：
2009-09-18
影响因子：
3.1
通讯作者：
Fish, Eleanor N.
中科院分区：
文献类型：
--
作者：
Murooka, Thomas T.;Rahbar, Ramtin;Fish, Eleanor N.
癌细胞的增殖能力受癌细胞固有的因子和微环境中的分泌因子的调节。在这里，我们研究了趋化因子受体CCR5在MCF-7乳腺癌细胞系中的原癌潜能。在生理水平上，CCR5的配体CCL5促进了MCF-7细胞的增殖。用mTOR抑制剂雷帕霉素处理可抑制CCL5诱导的这种增殖。由于mTOR直接调节mRNA的翻译，我们研究了CCL5激活CCR5是否导致翻译增加。CCL5通过mTOR依赖的过程诱导eIF4F翻译起始复合体的形成。事实上，CCL5启动了信使核糖核酸的翻译，表现为高分子量多聚体的增加。具体地说，我们发现CCL5介导了细胞周期蛋白D1、c-Myc和爸爸-1蛋白表达的快速上调，而不影响它们的mRNA水平。综上所述，我们描述了CCL5影响雷帕霉素敏感的mRNAs翻译的机制，从而为CCR5阳性的乳腺癌细胞提供了增殖优势。(C)2009 Elsevier Inc.保留所有权利。
The proliferative capacity of cancer cells is regulated by factors intrinsic to cancer cells and by secreted factors in the microenvironment. Here, we investigated the proto-oncogenic potential of the chemokine receptor, CCR5, in MCF-7 breast cancer cell lines. At physiological levels, CCL5, a ligand for CCR5, enhanced MCF-7.CCR5 proliferation. Treatment with the mTOR inhibitor, rapamycin, inhibited this CCL5-inducible proliferation. Because mTOR directly modulates mRNA translation, we investigated whether CCL5 activation of CCR5 leads to increased translation. CCL5 induced the formation of the eIF4F translation initiation complex through an mTOR-dependent process. Indeed, CCL5 initiated mRNA translation, shown by an increase in high-molecular-weight polysomes. Specifically, we show that CCL5 mediated a rapid up-regulation of protein expression for cyclin D1, c-Myc and Dad-1, without affecting their mRNA levels. Taken together, we describe a mechanism by which CCL5 influences translation of rapamycin-sensitive mRNAs, thereby providing CCR5-positive breast cancer cells with a proliferative advantage. (C) 2009 Elsevier Inc. All rights reserved.