Inhibition of mitogen-activated protein kinase kinase selectively inhibits cell proliferation in human breast cancer cells displaying enhanced insulin-like growth factor I-mediated mitogen-activated protein kinase activation.
Inhibition of mitogen-activated protein kinase kinase selectively inhibits cell proliferation in human breast cancer cells displaying enhanced insulin-like growth factor I-mediated mitogen-activated protein kinase activation.
复制标题
DOI：
--
复制
发表时间：
2000-12
期刊：
影响因子：
--
通讯作者：
Ulrich Hermanto;C. S. Zong;Lu‐Hai Wang
中科院分区：
文献类型：
--
作者：
Ulrich Hermanto;C. S. Zong;Lu‐Hai Wang
促分裂原活化蛋白（MAP）激酶通过调节由受体蛋白酪氨酸激酶（RPTK）（包括胰岛素样生长因子1受体（IGF-IR））激活的信号通路介导细胞增殖、细胞分化和细胞存活。我们分析了人乳腺癌细胞系中MAP激酶通路的上游信号成分，包括RPTKs，发现其中一些成分过表达。重要的是，发现导致MAP激酶途径的信号分子如IGF-IR、胰岛素受体和胰岛素受体底物1在某些肿瘤系中伴随过度表达，即，MCF-7和T-47 D。与非恶性和其他乳腺肿瘤细胞系相比，MCF-7和T-47 D细胞对胰岛素样生长因子I（IGF-I）刺激的反应更快、更强、更持久。相比之下，IGF-I治疗导致这些过度表达ErbB 2相关RPTKs的细胞系中MAP激酶的持续下调。有趣的是，在测试的正常细胞系和肿瘤细胞系中，用PD 098059阻断MAP激酶途径对MCF-7和T-47 D具有最大的抗增殖作用。此外，向生长培养基中添加IGF-IR阻断抗体减弱了PD 098059抑制MCF-7和T-47 D细胞生长的能力。因此，我们的研究表明，伴随着IGF-IR途径的多个信号传导组分的过度表达导致IGF-I介导的MAP激酶信号传导的放大，并导致对PD 098059的致敏。对PD 098059的敏感性增强意味着这些乳腺癌细胞对MAP激酶途径的需求增加，使该途径成为治疗选定乳腺恶性肿瘤的潜在靶点。
Mitogen-activated protein (MAP) kinase mediates cell proliferation, cell differentiation, and cell survival by regulating signaling pathways activated by receptor protein tyrosine kinases (RPTKs), including the insulin-like growth factor 1 receptor (IGF-IR). We analyzed the upstream signaling components of the MAP kinase pathway, including RPTKs, in human breast cancer cell lines and found that some of those components were overexpressed. Importantly, signaling molecules such as IGF-IR, insulin receptor, and insulin receptor substrate 1, leading to the MAP kinase pathway, were found to be concomitantly overexpressed within certain tumor lines, i.e., MCF-7 and T-47D. When compared with the nonmalignant and other breast tumor lines examined, MCF-7 and T-47D cells displayed a more rapid, robust, and sustained MAP kinase activation in response to insulin-like growth factor I (IGF-I) stimulation. By contrast, IGF-I treatment led to a sustained down-regulation of MAP kinase in those lines overexpressing ErbB2-related RPTKs. Interestingly, blocking the MAP kinase pathway with PD098059 had the greatest antiproliferative effect on MCF-7 and T-47D among the normal and tumor lines tested. Furthermore, addition of an IGF-IR blocking antibody to growth medium attenuated the ability of PD098059 to suppress the growth of MCF-7 and T-47D cells. Thus, our study suggests that concomitant overexpression of multiple signaling components of the IGF-IR pathway leads to the amplification of IGF-I-mediated MAP kinase signaling and resultant sensitization to PD098059. The enhanced sensitivity to PD098059 implies an increased requirement for the MAP kinase pathway in those breast cancer cells, making this pathway a potential target in the treatment of selected breast malignancies.