CNK1 Promotes Invasion of Cancer Cells through NF-κB-Dependent Signaling
CNK1 Promotes Invasion of Cancer Cells through NF-κB-Dependent Signaling
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DOI：
10.1158/1541-7786.mcr-09-0296
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发表时间：
2010-03-01
影响因子：
5.2
通讯作者：
Radziwill, Gerald
中科院分区：
文献类型：
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作者：
Fritz, Rafael D.;Radziwill, Gerald
癌细胞的标志是不受控制的增殖、逃避细胞凋亡、血管生成、细胞侵袭和转移，这些都是由信号通路的致癌激活驱动的。在此，我们将支架蛋白 CNK1 确定为致癌信号传导的介质，促进人类乳腺癌和宫颈癌细胞的侵袭。 CNK1 的下调可减少癌细胞的侵袭性，并与基质金属蛋白酶 9 (MMP-9) 和膜型 1 MMP (MT1-MMP) 表达的减少相关。 CNK1 的异位表达以 NF-κ B 依赖性方式提高 MT1-MMP 启动子活性。此外，CNK1与NF-kappa B通路合作，但不与细胞外信号调节蛋白激酶通路合作，促进细胞侵袭。从机制上讲，CNK1 调节 NF-kappa B 通路的替代分支，因为 CNK1 的敲低会干扰 NF-kappa B2 p100 到 p52 的加工及其在细胞核中的定位。与此一致的是，与对照细胞的侵袭相比，CNK1耗尽的细胞的侵袭对RelB下调的敏感性较低。此外，CNK1 依赖性 MT1-MMP 启动子激活被 RelB siRNA 阻断。因此，CNK1 是参与乳腺癌和宫颈癌细胞侵袭的致癌途径的重要介质，因此是癌症治疗的推定靶标。摩尔癌症研究中心； 8(3)； 395-406。 (C)2010 AACR。
Hallmarks of cancer cells are uncontrolled proliferation, evasion of apoptosis, angiogenesis, cell invasion, and metastasis, which are driven by oncogenic activation of signaling pathways. Herein, we identify the scaffold protein CNK1 as a mediator of oncogenic signaling that promotes invasion in human breast cancer and cervical cancer cells. Downregulation of CNK1 diminishes the invasiveness of cancer cells and correlates with reduced expression of matrix metalloproteinase 9 (MMP-9) and membrane-type 1 MMP (MT1-MMP). Ectopic expression of CNK1 elevates MT1-MMP promoter activity in a NF-kappa B-dependent manner. Moreover, CNK1 cooperates with the NF-kappa B pathway, but not with the extracellular signal-regulated protein kinase pathway, to promote cell invasion. Mechanistically, CNK1 regulates the alternative branch of the NF-kappa B pathway because knockdown of CNK1 interferes with processing of NF-kappa B2 p100 to p52 and its localization to the nucleus. In agreement with this, the invasion of CNK1-depleted cells is less sensitive to RelB downregulation compared with the invasion of control cells. Moreover, CNK1-dependent MT1-MMP promoter activation is blocked by RelB siRNA. Thus, CNK1 is an essential mediator of an oncogenic pathway involved in invasion of breast and cervical cancer cells and is therefore a putative target for cancer therapy. Mol Cancer Res; 8(3); 395-406. (C)2010 AACR.