Hamadmad Sumaya N, Hohl Raymond J
Department of Internal Medicine, SE 313 GH, University of Iowa, Iowa City, IA 52242, USA.
J Pharmacol Exp Ther. 2008 Mar;324(3):1227-33. doi: 10.1124/jpet.107.129643. Epub 2007 Dec 13.
Erythropoietin (Epo) receptor (EpoR) is expressed in several cancer cell lines, and the functional consequence of this expression is under extensive study. In this study, we used a cervical cancer cell line in which EpoR was first found to be expressed and to correlate with the severity of the disease. We demonstrate that Epo is a chemoattractant for these cancer cells, enhancing their migration under serum-starved conditions. Using a Transwell migration system, we show that Epo enhances cancer cell migration in a dose- and time-dependent manner. The effect of Epo is dependent on the activity of two signaling pathways: the mitogen-activated protein kinase (MAPK) pathway and the RhoA GTPase pathway. We show that Epo activates both pathways in a Janus kinase-dependent manner and that this activation is required for Epo effects on cell migration. Furthermore, we use both pharmacological and genetic inhibitors to demonstrate that the activation of RhoA GTPase is dependent on the activity of the MAPK pathway, providing the first evidence for interaction between these two signaling cascades.
促红细胞生成素（Epo）受体（EpoR）在多种癌细胞系中表达，这种表达的功能后果正在进行广泛研究。在本研究中，我们使用了一种首次发现EpoR表达且其与疾病严重程度相关的宫颈癌细胞系。我们证明Epo是这些癌细胞的趋化因子，在血清饥饿条件下增强其迁移能力。使用Transwell迁移系统，我们表明Epo以剂量和时间依赖性方式增强癌细胞迁移。Epo的作用取决于两条信号通路的活性：丝裂原活化蛋白激酶（MAPK）通路和RhoA GTP酶通路。我们表明Epo以Janus激酶依赖性方式激活这两条通路，并且这种激活是Epo对细胞迁移产生作用所必需的。此外，我们使用药理学和基因抑制剂来证明RhoA GTP酶的激活依赖于MAPK通路的活性，这为这两条信号级联之间的相互作用提供了首个证据。
