Urokinase is a Negative Modulator of Egf-dependent Proliferation and Motility in the Two Breast Cancer Cell Lines MCF-7 and MDA-MB-231
Urokinase is a Negative Modulator of Egf-dependent Proliferation and Motility in the Two Breast Cancer Cell Lines MCF-7 and MDA-MB-231
复制标题
DOI：
10.1002/mc.22267
复制
发表时间：
2016-02-01
影响因子：
4.6
通讯作者：
Kietzmann, Thomas
中科院分区：
文献类型：
--
作者：
Kozlova, Nina;Samoylenko, Anatoly;Kietzmann, Thomas
表皮生长因子受体（EGFR）参与多种细胞过程的调节，其信号传导的失调在多种恶性肿瘤如乳腺癌的病因学中起关键作用。与此同时，尿激酶（uPA），其受体uPAR和纤溶酶原激活系统的其他成分的水平升高被发现与乳腺癌的预后不良相关。有趣的是，EGFR似乎参与转导uPA与uPAR结合后产生的信号。然而，uPA信号传导是否会因此干扰配体驱动的EGFR信号传导之前没有描述。因此，本研究的目的是研究uPA和EGF在低侵袭性和高侵袭性乳腺癌细胞系MCF-7和MDA-MB-231中的联合作用。细胞同时暴露于两种信号对ERK 1/2和AKT活化产生负面影响，而对p38和Src激酶磷酸化产生正面影响。此外，uPA减弱EGF对MCF-7和MDA-MB-231细胞的增殖、侵袭和运动的促有丝分裂作用。用uPA氨基末端片段（ATF）进行的实验表明，uPA的负面影响与其蛋白酶活性无关。总之，这些数据表明，乳腺癌中uPA水平的提高可调节EGF的促有丝分裂作用，因此，这一知识可能有助于更好地了解乳腺癌发病机制以及开发新的治疗方案。(C)2015 Wiley Periodicals，Inc.
The epidermal growth factor receptor (EGFR) is involved in the regulation of various cellular processes and dysregulation of its signalling plays a critical role in the etiology of a variety of malignancies like breast cancer. At the same time, elevated levels of urokinase (uPA), its receptor uPAR, and other components of the plasminogen activation system are found to be correlated with a poor prognosis in breast cancer. Interestingly, EGFR appears to participate in transducing the signal generated upon binding of uPA to uPAR. However, whether uPA signalling would thereby interfere with ligand-driven EGFR signalling was not described before. Therefore, it was the aim of the present study to investigate the combined effects of uPA and EGF in the low invasive and high invasive breast adenocarcinoma cell lines MCF-7 and MDA-MB-231, respectively. Simultaneous exposure of cells to both signals negatively affected ERK1/2 and AKT activation whereas positive effects on p38 and Src kinase phosphorylation were noted in both cell lines. Furthermore, uPA attenuated the mitogenic effect of EGF on cellular proliferation, invasion and motility in both MCF-7 and MDA-MB-231 cells. Experiments with the uPA amino terminal fragment (ATF) revealed that the negative effects of uPA were independent from its protease activity. Together, these data suggest that enhanced levels of uPA in breast cancer modulate the mitogenic effects of EGF and thus, this knowledge may help to better understand breast cancer pathogenesis as well as to develop new therapeutic options. (C) 2015 Wiley Periodicals, Inc.