Growth and motility inhibition of breast cancer cells by epidermal growth factor receptor degradation is correlated with inactivation of Cdc42
Growth and motility inhibition of breast cancer cells by epidermal growth factor receptor degradation is correlated with inactivation of Cdc42
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DOI：
10.1158/0008-5472.can-05-1547
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发表时间：
2006-04-01
期刊：
影响因子：
11.2
通讯作者：
Wu, WJ
中科院分区：
文献类型：
--
作者：
Hirsch, DS;Shen, Y;Wu, WJ
表皮生长因子受体（EGFR）的过表达有助于乳腺癌细胞增殖和迁移的增加。然而，EGFR过表达的机制仍然难以捉摸，通常不能归因于基因扩增。在NIH 3 T3成纤维细胞中，活性Cdc 42抑制c-CIA调节的EGFR降解以诱导细胞转化。在这里，我们使用两个EGFR过表达的乳腺癌细胞系，MDA-MB-231和BT 20，其模型来测试的假设，上调Cdc 42活性损害c-Cbl介导的EGFR降解，并有助于EGFR过表达。我们发现，沉默Cdc 42显着降低EGFR的蛋白水平，导致细胞增殖和迁移的显着减少，c-Cbl敲除增加EGFR的水平。c-Cbl-N480是一种不受Cdc 42调控并阻断Cdc 42诱导的转化但仍结合并泛素化EGFR的c-Cbl突变体，其表达增强EGFR降解速率并随后抑制细胞增殖。此外，c-Cbl-N480诱导的EGFR信号转导下调降低Cdc 42和Rac 1的活性，导致细胞迁移抑制。这些发现表明Cdc 42和c-Cbl是参与调节EGFR蛋白水平的关键组分，并且通过破坏Cdc 42对c-Cbl的调节来恢复适当的EGFR降解可以减少MDA-MB-231和BT 20细胞中的细胞增殖和迁移。
Overexpression of epidermal growth factor receptor (EGFR) contributes to increased cell proliferation and migration in breast cancer. However, mechanisms of EGFR overexpression remain elusive and often cannot be attributed to gene amplification. In NIH3T3 fibroblasts, active Cdc42 inhibits c-CIA-regulated EGFR degradation to induce cellular transformation. Here, we use two EGFR-overexpressing breast cancer cell lines, MDA-MB-231 and BT20, its models to test the hypothesis that up-regulated Cdc42 activity impairs c-Cbl-mediated EGFR degradation and contributes to EGFR overexpression. We show that silencing Cdc42 significantly reduces protein levels of EGFR, leading to a marked reduction in cell proliferation and migration, and c-Cbl knockdown increases the levels of EGFR. Expression of c-Cbl-N480, a c-Cbl mutant that is not regulated by Cdc42 and blocks Cdc42-induced transformation but still binds and ubiquitinates EGFR, enhances the rate of EGFR degradation and subsequently inhibits cell proliferation. Moreover, down-regulated EGFR signaling induced by c-Cbl-N480 decreased activity of Cdc42 and Rac1, resulting in inhibition of cell migration. These findings indicate that Cdc42 and c-Cbl are critical components involved in the regulation of EGFR protein levels anti that restoration of proper EGFR degradation by disrupting Cdc42 regulation of c-Cbl can reduce cell proliferation and migration in MDA-MB-231 and BT20 cells.