Activated protein C enhances cell motility of endothelial cells and MDA-MB-231 breast cancer cells by intracellular signal transduction.
Activated protein C enhances cell motility of endothelial cells and MDA-MB-231 breast cancer cells by intracellular signal transduction.
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DOI：
10.1016/j.yexcr.2009.10.024
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发表时间：
2010-02-01
影响因子：
3.7
通讯作者：
Church FC
中科院分区：
文献类型：
--
作者：
Gramling MW;Beaulieu LM;Church FC
活化蛋白C（APC）是一种抗凝丝氨酸蛋白酶，已被证明具有与炎症、细胞存活和细胞迁移相关的非止血功能。在这项研究中，我们调查的机制，APC促进血管生成和乳腺癌的侵袭使用离体和体外方法。当具有蛋白水解活性时，APC促进内皮细胞的细胞运动/侵袭和管形成。离体主动脉环测定验证了APC在促进血管生成中的作用，其被确定为依赖于EGFR和MMP活化。考虑到APC促进血管生成的能力以及这一过程在癌症病理学中的重要性，我们研究了APC促进血管生成的机制是否也能促进MDA-MB-231乳腺癌细胞系的运动性和侵袭性。我们的研究结果表明，在细胞外，APC参与EPCR，PAR-1和EGFR，以增加MDA-MB-231细胞的侵袭力。APC激活基质金属蛋白酶（MMP）-2和/或-9是必需的，但不足以增加侵袭，并且APC不利用内源性纤溶酶原激活系统来增加侵袭。在细胞内，APC激活ERK、Akt和NFκB，但不激活JNK通路，以促进MDA-MB-231细胞运动。与止血蛋白酶凝血酶类似，APC具有增强内皮细胞运动性/血管生成和乳腺癌细胞迁移的能力。
Activated protein C (APC), an anticoagulant serine protease, has been shown to have non-hemostatic functions related to inflammation, cell survival, and cell migration. In this study we investigate the mechanism by which APC promotes angiogenesis and breast cancer invasion using ex vivo and in vitro methods. When proteolytically active, APC promotes cell motility/invasion and tube formation of endothelial cells. Ex vivo aortic ring assays verify the role of APC in promoting angiogenesis, which was determined to be dependent on EGFR and MMP activation. Given the capacity of APC to promote angiogenesis and the importance of this process in cancer pathology, we investigated whether the mechanisms by which APC promotes angiogenesis can also promote motility and invasion in the MDA-MB-231 breast cancer cell line. Our results indicate that, extracellularly, APC engages EPCR, PAR-1, and EGFR in order to increase the invasiveness of MDA-MB-231 cells. APC activation of matrix metalloprotease (MMP) -2 and/or -9 is necessary but not sufficient to increase invasion, and APC does not utilize the endogenous plasminogen activation system to increase invasion. Intracellularly, APC activates ERK, Akt, and NFκB, but not the JNK pathway to promote MDA-MB-231 cell motility. Similar to the hemostatic protease thrombin, APC has the ability to enhance both endothelial cell motility/angiogenesis and breast cancer cell migration.
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