Institute of Medical Virology, University of Zurich, Zurich, Switzerland.
Mol Cancer Res. 2010 Mar;8(3):395-406. doi: 10.1158/1541-7786.MCR-09-0296. Epub 2010 Mar 2.
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-kappaB-dependent manner. Moreover, CNK1 cooperates with the NF-kappaB pathway, but not with the extracellular signal-regulated protein kinase pathway, to promote cell invasion. Mechanistically, CNK1 regulates the alternative branch of the NF-kappaB pathway because knockdown of CNK1 interferes with processing of NF-kappaB2 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.
癌细胞的特征是不受控制的增殖、逃避细胞凋亡、血管生成、细胞侵袭和转移，这些特征是由信号通路的致癌激活驱动的。在此，我们确定支架蛋白 CNK1 为促进人类乳腺癌和宫颈癌细胞侵袭的致癌信号转导的介质。CNK1 的下调可降低癌细胞的侵袭性，并与基质金属蛋白酶 9（MMP-9）和膜型 1 MMP（MT1-MMP）的表达降低相关。CNK1 的异位表达以 NF-kappaB 依赖性方式升高 MT1-MMP 启动子活性。此外，CNK1 与 NF-kappaB 途径协同作用，而不是与细胞外信号调节蛋白激酶途径协同作用，促进细胞侵袭。从机制上讲，CNK1 调节 NF-kappaB 途径的替代分支，因为 CNK1 的敲低会干扰 NF-kappaB2 p100 向 p52 的加工及其向核内的定位。与此一致的是，与对照细胞相比，CNK1 耗尽细胞的侵袭对 RelB 下调的敏感性降低。此外，RelB siRNA 阻断了依赖于 CNK1 的 MT1-MMP 启动子激活。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，因此是癌症治疗的潜在靶标。
