Inhibition of Src family kinases with dasatinib blocks migration and invasion of human melanoma cells.
Inhibition of Src family kinases with dasatinib blocks migration and invasion of human melanoma cells.
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DOI：
10.1158/1541-7786.mcr-08-0169
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发表时间：
2008-11
期刊：
影响因子：
--
通讯作者：
Jove R
中科院分区：
文献类型：
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作者：
Buettner R;Mesa T;Vultur A;Lee F;Jove R
Src家族激酶（SFK）参与调节多种生物学过程，包括细胞粘附、迁移、增殖和存活，这取决于细胞环境。因此，尽管SFK目前正在作为各种癌症治疗策略的潜在靶点进行研究，但在任何给定的肿瘤类型中抑制SFK信号传导的生物学反应都是不可预测的。达沙替尼（BMS-354825）是一种Src/Abl双重激酶抑制剂，对BCR-ABL活化的恶性血液病具有有效的抗增殖活性。此外，在研究的所有8种人黑色素瘤细胞系中，达沙替尼在低纳摩尔浓度下完全抑制SFK激酶活性。此外，SFKs的两个已知下游靶标，粘着斑激酶（FAK）和Crk相关底物（p130 CAS），以相似的浓度和动力学被抑制。与抑制这些信号通路和侵袭一致，达沙替尼下调基质金属蛋白酶-9（MMP-9）的表达。我们还提供了证据表明，达沙替尼直接抑制EphA 2受体酪氨酸激酶的激酶活性，EphA 2受体酪氨酸激酶在许多实体瘤（包括黑色素瘤）中过表达和/或过度活跃。因此，Src家族激酶和下游信号传导被认为在黑素瘤细胞的迁移和侵袭中具有关键作用。
Src family kinases (SFKs) are involved in regulating a multitude of biological processes including cell adhesion, migration, proliferation and survival, depending on the cellular context. Therefore, although SFKs are currently being investigated as potential targets for treatment strategies in various cancers, the biological responses to inhibition of SFK signaling in any given tumor type are not predictable. Dasatinib (BMS-354825) is a dual Src/Abl kinase inhibitor with potent antiproliferative activity against hematologic malignancies harboring activated BCR-ABL. In this study, we show that dasatinib blocks migration and invasion of human melanoma cells without affecting proliferation and survival. Moreover, dasatinib completely inhibits SFK kinase activity at low nanomolar concentrations in all 8 human melanoma cell lines investigated. In addition, two known downstream targets of SFKs, focal adhesion kinase (FAK) and Crk-associated substrate (p130CAS), are inhibited with similar concentrations and kinetics. Consistent with inhibition of these signaling pathways and invasion, dasatinib down-regulates expression of matrix metalloproteinase-9 (MMP-9). We also provide evidence that dasatinib directly inhibits kinase activity of the EphA2 receptor tyrosine kinase, which is overexpressed and/or overactive in many solid tumors including melanoma. Thus, Src family kinases and downstream signaling are implicated as having key roles in migration and invasion of melanoma cells.