Department of Oncogene Research, Research Institute for Microbial Diseases, Osaka University. 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.
Mol Cancer Res. 2011 Jan;9(1):103-14. doi: 10.1158/1541-7786.MCR-10-0340. Epub 2010 Dec 14.
The tyrosine kinase c-Src is upregulated in various human cancers, although the precise regulatory mechanism underlying this upregulation is unclear. We previously reported that a transmembrane adaptor Csk-binding protein (Cbp; PAG1) plays an important role in controlling the cell transformation that is induced by the activation of c-Src. To elucidate the in vivo role of Cbp, we examined the function of Cbp in lung cancer cell lines and tissues. In this study, we found that Cbp was markedly downregulated in human non-small cell lung cancer (NSCLC) cells. The ectopic expression of Cbp suppressed the anchorage-independent growth of the NSCLC cell lines (A549 and Lu99) that had upregulated c-Src, whereas the Cbp expression had little effect on other NSCLC cell lines (PC9 and Lu65) that express normal levels of c-Src. The expression of Cbp suppressed the kinase activity of c-Src in A549 cells by recruiting c-Src and its negative regulator, C-terminal Src kinase (Csk), to lipid rafts. The treatment with Src inhibitors, such as PP2, dasatinib, and saracatinib, also suppressed the growth of A549 cells. Furthermore, Cbp expression attenuated the ability of A549 cells to form tumors in nude mice, invade in vitro, and metastasize in vivo. In addition, we found a significant inverse correlation between the level of Cbp expression and the extent of lymph node metastasis in human lung cancers. These results indicate that Cbp is required for the Csk-mediated inactivation of c-Src and may control the promotion of malignancy in NSCLC tumors that are characterized by c-Src upregulation.
酪氨酸激酶 c-Src 在各种人类癌症中上调，尽管这种上调的确切调节机制尚不清楚。我们之前报道过，跨膜衔接蛋白 Csk 结合蛋白（Cbp；PAG1）在控制 c-Src 激活诱导的细胞转化中发挥重要作用。为了阐明 Cbp 的体内作用，我们研究了 Cbp 在肺癌细胞系和组织中的功能。在这项研究中，我们发现 Cbp 在人类非小细胞肺癌（NSCLC）细胞中明显下调。Cbp 的异位表达抑制了上调 c-Src 的 NSCLC 细胞系（A549 和 Lu99）的非锚定依赖性生长，而 Cbp 的表达对表达正常水平 c-Src 的其他 NSCLC 细胞系（PC9 和 Lu65）几乎没有影响。Cbp 通过募集 c-Src 和其负调节剂 C 末端Src 激酶（Csk）到脂筏，抑制 A549 细胞中 c-Src 的激酶活性。Src 抑制剂，如 PP2、dasatinib 和 saracatinib 的处理也抑制了 A549 细胞的生长。此外，Cbp 表达减弱了 A549 细胞在裸鼠中形成肿瘤、体外侵袭和体内转移的能力。此外，我们发现 Cbp 表达水平与人类肺癌淋巴结转移程度之间存在显著的负相关。这些结果表明 Cbp 是 Csk 介导的 c-Src 失活所必需的，可能控制着由 c-Src 上调引起的 NSCLC 肿瘤恶性程度的增加。
