Activation of Abl tyrosine kinases promotes invasion of aggressive breast cancer cells
Activation of Abl tyrosine kinases promotes invasion of aggressive breast cancer cells
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DOI：
10.1158/0008-5472.can-06-0734
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发表时间：
2006-06-01
期刊：
影响因子：
11.2
通讯作者：
Plattner, Rina
中科院分区：
文献类型：
--
作者：
Srinivasan, Divyamani;Plattner, Rina
非受体酪氨酸激酶Abl家族由两个相关蛋白质c-Abl和c-Abl相关基因（Arg）组成。激活形式的Abl激酶（BCR-Abl、Tel-Abl和Tel-Arg）诱导人类白血病的发生;然而，Abl激酶是否在实体瘤中被激活或是否有助于肿瘤的发生或进展尚不清楚。以前，我们表明，Abl激酶激活下游的生长因子受体，Src家族激酶，和磷脂酶C γ 1（PLC γ 1）在成纤维细胞和影响生长因子介导的增殖，膜皱褶，和迁移。生长因子受体、Sire激酶和PLC γ 1在许多实体瘤中失调并驱动肿瘤侵袭和转移。在这项研究中，我们发现，Abl激酶组成性激活，在高度侵袭性乳腺癌细胞系，下游的ErbB受体和Sire激酶失调。此外，Abl激酶的活化促进乳腺癌细胞侵袭，因为用Abl激酶抑制剂STI 571处理细胞或用RNA干扰沉默c-Abl和Arg表达显著抑制基质胶侵袭。这是第一个证据表明：（a）Abl激酶在非造血系统癌症中被失调和激活，（B）Abl激酶在乳腺癌细胞中的激活通过一种新的机制发生，和（c）Abl激酶的组成性激活促进乳腺癌细胞的侵袭。这些数据表明，针对Abl激酶的药理学抑制剂可能在预防携带激活的Abl激酶的肿瘤中的乳腺癌进展中是有用的。
The Abl family of nonreceptor tyrosine kinases consists of two related proteins, c-Abl and Abl-related gene (Arg). Activated forms of the Abl kinases (BCR-Abl, Tel-Abl, and Tel-Arg) induce the development of human leukemia; it is not known, however, whether Abl kinases are activated in solid tumors or whether they contribute to tumor development or progression. Previously, we showed that Abl kinases are activated downstream of growth factor receptors, Src family kinases, and phospholipase C gamma 1 (PLC gamma l) in fibroblasts and influence growth factor-mediated proliferation, membrane ruffling, and migration. Growth factor receptors, Sire kinases, and PLC gamma 1 are deregulated in many solid tumors and drive tumor invasion and metastasis. In this study, we found that Abl kinases are constitutively activated, in highly invasive breast cancer cell lines, downstream of deregulated ErbB receptors and Sire kinases. Furthermore, activation of Abl kinases promotes breast cancer cell invasion, as treatment of cells with the Abl kinase inhibitor, STI571, or silencing c-Abl and Arg expression with RNA interference dramatically inhibits Matrigel invasion. This is the first evidence that (a) Abl kinases are deregulated and activated in a nonhematopoietic cancer, (b) activation of Abl kinases in breast cancer cells occurs via a novel mechanism, and (c) constitutive activation of Abl kinases promotes invasion of breast cancer cells. These data suggest that pharmacologic inhibitors targeted against Abl kinases could potentially be useful in preventing breast cancer progression in tumors harboring activated Abl kinases.