Chen Ting, Pengetnze Yolande, Taylor Christopher C
Department of Cell Biology, Vincent T. Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, 3900 Reservoir Road, Washington, D.C. 20007, USA.
Mol Cancer Ther. 2005 Feb;4(2):217-24.
Src tyrosine kinase has been found to be overexpressed and activated in a high proportion of ovarian cancers and ovarian cancer cell lines. Furthermore, Src activation is associated with activation of growth and survival signaling pathways. The present study was conducted in order to determine the effects of Src inhibition on ovarian cancer cell survival in response to chemotherapeutic agents. Inhibition of Src, either pharmacologically or through expression of a Src dominant-negative fusion construct, enhanced the cytotoxicity of two different classes of chemotherapeutics: paclitaxel and cisplatinum, in both mouse and human ovarian cancer cells. Interestingly, Src inhibition also restored sensitivity to drug-resistant ovarian cancer cells. The increased cytotoxicity in response to Src inhibition was associated with a large increase in processing and activation of caspase-3. The activation of caspase-3 seems to be independent of cytochrome c release and caspase-9 activation. The present study indicates that Src tyrosine kinase may provide an important target for small molecule inhibition in ovarian cancer.
已发现Src酪氨酸激酶在高比例的卵巢癌和卵巢癌细胞系中过表达并被激活。此外，Src激活与生长和生存信号通路的激活相关。进行本研究以确定Src抑制对卵巢癌细胞对化疗药物反应中细胞存活的影响。通过药理学方法或通过表达Src显性负性融合构建体抑制Src，均可增强两种不同类型化疗药物（紫杉醇和顺铂）对小鼠和人卵巢癌细胞的细胞毒性。有趣的是，Src抑制还恢复了对耐药卵巢癌细胞的敏感性。Src抑制后细胞毒性增加与caspase-3的加工和激活大幅增加有关。caspase-3的激活似乎独立于细胞色素c释放和caspase-9激活。本研究表明，Src酪氨酸激酶可能为卵巢癌小分子抑制提供重要靶点。
