Srinivasan Divyamani, Plattner Rina
Department of Molecular and Biomedical Pharmacology, University of Kentucky School of Medicine, Lexington, Kentucky, USA.
Cancer Res. 2006 Jun 1;66(11):5648-55. doi: 10.1158/0008-5472.CAN-06-0734.
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 Cgamma1 (PLCgamma1) in fibroblasts and influence growth factor-mediated proliferation, membrane ruffling, and migration. Growth factor receptors, Src kinases, and PLCgamma1 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 Src 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.
非受体酪氨酸激酶Abl家族由两种相关蛋白组成，即c-Abl和Abl相关基因（Arg）。Abl激酶的激活形式（BCR-Abl、Tel-Abl和Tel-Arg）可诱导人类白血病的发生；然而，尚不清楚Abl激酶在实体瘤中是否被激活，以及它们是否促进肿瘤的发生或进展。此前，我们发现Abl激酶在成纤维细胞中生长因子受体、Src家族激酶和磷脂酶Cγ1（PLCγ1）的下游被激活，并影响生长因子介导的增殖、膜皱襞形成和迁移。生长因子受体、Src激酶和PLCγ1在许多实体瘤中失调，并驱动肿瘤侵袭和转移。在本研究中，我们发现Abl激酶在高度侵袭性乳腺癌细胞系中，在失调的ErbB受体和Src激酶的下游持续被激活。此外，Abl激酶的激活促进乳腺癌细胞侵袭，因为用Abl激酶抑制剂STI571处理细胞，或用RNA干扰沉默c-Abl和Arg的表达，可显著抑制基质胶侵袭。这是首个表明（a）Abl激酶在非造血系统癌症中失调并被激活，（b）乳腺癌细胞中Abl激酶的激活通过一种新机制发生，以及（c）Abl激酶的持续激活促进乳腺癌细胞侵袭的证据。这些数据表明，针对Abl激酶的药物抑制剂可能有助于预防Abl激酶激活的肿瘤中的乳腺癌进展。
