CXCL-12/stromal cell-derived factor-1α transactivates HER2-neu in breast cancer cells by a novel pathway involving Src kinase activation
CXCL-12/stromal cell-derived factor-1α transactivates HER2-neu in breast cancer cells by a novel pathway involving Src kinase activation
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DOI：
10.1158/0008-5472.can-04-1303
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发表时间：
2005-08-01
期刊：
影响因子：
11.2
通讯作者：
Price, JE
中科院分区：
文献类型：
--
作者：
Cabioglu, N;Summy, J;Price, JE
实验证据表明，CXCR 4，一种配体CXCL 12/基质细胞衍生因子-lot（SDF-1 α）的G（i）蛋白偶联受体，在乳腺癌转移中发挥作用。据报道，G蛋白偶联受体激活对HER 2-neu的反式激活是激活酪氨酸激酶受体的配体非依赖性机制。我们发现SDF-1 α在乳腺癌细胞系MDA-MB-361和SKBR 3中反式激活HER 2-neu，这两种细胞系同时表达CXCR 4和HER 2-neu。CXCR 4抑制剂AMD 3100、表皮生长因子受体/HER 2-neu酪氨酸激酶抑制剂PKI 166和Src激酶抑制剂PP 2均阻断SM-1 α诱导的HER 2-neu磷酸化。用PP 2阻断Src激酶或使用激酶失活的Src构建体，以及用PKI 166抑制表皮生长因子受体/HER 2-neu信号传导均抑制SDF-1 α刺激的细胞迁移。我们报告了一种新的机制，HER 2-neu反式激活通过SDF-1 α刺激CXCR 4，涉及Src激酶激活。
Experimental evidence suggests that CXCR4, a G(i) protein-coupled receptor for the ligand CXCL12/stromal cell-derived factor-lot (SDF-1 alpha), plays a role in breast cancer metastasis. Transactivation of HER2-neu by G protein-coupled receptor activation has been reported as a ligand-independent mechanism of activating tyrosine kinase receptors. We found that SDF-1 alpha transactivated HER2-neu in the breast cancer cell lines MDA-MB-361 and SKBR3, which express both CXCR4 and HER2-neu. AMD3100, a CXCR4 inhibitor, PKI 166, an epidermal growth factor receptor/HER2-neu tyrosine kinase inhibitor, and PP2, a Src kinase inhibitor, each blocked SM-1 alpha-induced HER2-neu phosphorylation. Blocking Src kinase, with PP2 or using a kinase-inactive Src construct, and inhibiting epidermal growth factor receptor/HER2-neu signaling with PKI 166 each inhibited SDF-1 alpha-stimulated cell migration. We report a novel mechanism of HER2-neu transactivation through SDF-1 alpha stimulation of CXCR4 that involves Src kinase activation.