N,N′-Dinitrosopiperazine-mediated Ezrin Protein Phosphorylation via Activation of Rho Kinase and Protein Kinase C Is Involved in Metastasis of Nasopharyngeal Carcinoma 6-10B Cells
N,N′-Dinitrosopiperazine-mediated Ezrin Protein Phosphorylation via Activation of Rho Kinase and Protein Kinase C Is Involved in Metastasis of Nasopharyngeal Carcinoma 6-10B Cells
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DOI：
10.1074/jbc.m111.259234
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发表时间：
2011-10-21
影响因子：
4.8
通讯作者：
Dong, Zigang
中科院分区：
文献类型：
--
作者：
Tang, Faqing;Zou, Feiyan;Dong, Zigang
N，N‘-二亚硝基哌嗪(DNP)是一种对鼻咽上皮具有器官特异性的鼻咽癌致癌物质。在这里，我们证明了DNP诱导鼻咽癌细胞(6-10B)的纤维形成，并增加了6-10B细胞的侵袭性和运动性。在裸鼠体内也证实了DNP介导的鼻咽癌转移。重要的是，DNP以剂量和时间依赖的方式诱导苏氨酸567(Thr-567)磷酸化的Ezrin(Phos-Ezrin)的表达，但对总Ezrin的表达没有影响。此外，DNP诱导的PHos-Ezrin的表达依赖于Rho激酶和蛋白激酶C(PKC)活性的增加。在体内，DNP可能通过与其Pleckstrin同源物结合而激活Rho激酶，也可能通过促进PKC向质膜转位而激活PKC。DNP诱导的Phos-Ezrin与诱导6-10B细胞的纤维生长有关。然而，DNP不能诱导含有Thr-567突变的Ezrin的鼻咽癌细胞的运动和侵袭。同样，DNP不能诱导含有针对Rho或PKC的siRNAs的细胞的运动和侵袭。这些结果表明，DNP诱导Thr-567上的Ezrin磷酸化，增加细胞的运动性和侵袭性，促进肿瘤转移。DNP可能通过调节Thr-567位Ezrin的磷酸化参与鼻咽癌的转移。
N,N'-Dinitrosopiperazine (DNP) is a carcinogen for nasopharyngeal carcinoma (NPC), which shows organ specificity to nasopharyngeal epithelium. Herein, we demonstrate that DNP induces fiber formation of NPC cells (6-10B) and also increases invasion and motility of 6-10B cells. DNP-mediated NPC metastasis also was confirmed in nude mice. Importantly, DNP induced the expression of phosphorylated ezrin (phos-ezrin) at threonine 567 (Thr-567) dose-and time-dependently but had no effect on the total ezrin expression at these concentrations. Furthermore, DNP-induced phos-ezrin expression was dependent on increased Rho kinase and protein kinase C (PKC) activity. DNP may activate Rho kinase through binding to its pleckstrin homology and may activate PKC through promoting its translocation to the plasma membrane in vivo. DNP-induced phos-ezrin was associated with induction of fiber growth in 6-10B cells. However, DNP could not induce motility and invasion of NPC cells containing ezrin mutated at Thr-567. Similarly, DNP could not induce motility and invasion of the cells containing siRNAs against Rho or PKC. These results indicate that DNP induces ezrin phosphorylation at Thr-567, increases motility and invasion of cells, and promotes tumor metastasis. DNP may be involved in NPC metastasis through regulation of ezrin phosphorylation at Thr-567.