SKI-606 (bosutinib), a novel Src kinase inhibitor, suppresses migration and invasion of human breast cancer cells
SKI-606 (bosutinib), a novel Src kinase inhibitor, suppresses migration and invasion of human breast cancer cells
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DOI：
10.1158/1535-7163.mct-08-0126
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发表时间：
2008-05-01
影响因子：
5.7
通讯作者：
Jove, Richard
中科院分区：
文献类型：
--
作者：
Vultur, Adina;Buettner, Ralf;Jove, Richard
Src家族激酶活性在包括乳腺癌在内的许多人类肿瘤中升高，并且通常与侵袭性疾病相关。我们研究了选择性Src家族激酶抑制剂SKI-606（博舒替尼）对乳腺癌患者衍生的人类癌细胞的影响，以评估其治疗乳腺癌的潜力。我们的研究结果表明，SKI-606引起乳腺癌细胞系细胞运动和侵袭的减少，其IC50近似于250 nmol/L，这也是抑制完整肿瘤细胞Src激酶活性的IC50。这些变化伴随着细胞间粘附和β -连环蛋白膜定位的增加。相反，当SKI-606浓度足以阻断细胞迁移和侵袭时，细胞增殖和存活不受影响。Src的下游效应物分析显示，SKI-606抑制局灶黏附激酶（FAK）、富含脯氨酸的酪氨酸激酶2 （Pyk2）和crk相关底物（p130(Cas)）的磷酸化，IC50与细胞Src激酶的抑制相似。我们的研究结果表明，SKI-606抑制参与控制肿瘤细胞运动和侵袭的信号通路，表明SKI-606是一种有前景的乳腺癌治疗药物。
Src family kinase activity is elevated in many human tumors, including breast cancer, and is often associated with aggressive disease. We examined the effects of SKI-606 (bosutinib), a selective Src family kinase inhibitor, on human cancer cells derived from breast cancer patients to assess its potential for breast cancer treatment. Our results show that SKI-606 caused a decrease in cell motility and invasion of breast cancer cell lines with an IC50 of similar to 250 nmol/L, which was also the IC50 for inhibition of cellular Src kinase activity in intact tumor cells. These changes were accompanied by an increase in cell-to-cell adhesion and membrane localization of beta-catenin. By contrast, cell proliferation and survival were unaffected by SKI-606 at concentrations sufficient to block cell migration and invasion. Analysis of downstream effectors of Src revealed that SKI-606 inhibits the phosphorylation of focal adhesion kinase (FAK), proline-rich tyrosine kinase 2 (Pyk2), and Crk-associated substrate (p130(Cas)), with an IC50 similar to inhibition of cellular Src kinase. Our findings indicate that SKI-606 inhibits signaling pathways involved in controlling tumor cell motility and invasion, suggesting that SKI-606 is a promising therapeutic for breast cancer.