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PAR1介导的RhoA激活促进CCL2诱导的PC-3细胞趋化作用。

PAR1-mediated RhoA activation facilitates CCL2-induced chemotaxis in PC-3 cells.

作者信息

Loberg Robert D, Tantivejkul Kwanchanit, Craig Matthew, Neeley Chris K, Pienta Kenneth J

机构信息

Department of Urology, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan 48109, USA.

出版信息

J Cell Biochem. 2007 Aug 1;101(5):1292-300. doi: 10.1002/jcb.21252.

Abstract

Patients with advanced prostate cancer often exhibit increased activation of the coagulation system. The key activator of the coagulation cascade is the serine protease thrombin which is capable of eliciting numerous cellular responses. We previously reported that the thrombin receptor PAR1 is overexpressed in prostate cancer. To investigate further the role of PAR1 in prostate cancer metastasis, we examined the effects of thrombin activation on cell adhesion and motility in PC-3 prostate cancer cells. Activation of PAR1-induced dynamic cytoskeletal reorganization and reduced PC-3 binding to collagen I, collagen IV, and laminin (P < 0.01) but not fibronectin. Expression of the cell surface integrin receptors did not change as assessed by flow cytometry. Immunofluorescence microscopy revealed that PAR1 stimulation caused reorganization of the focal adhesions, suggesting that PAR1 activation in PC-3 cells may be modulating cell adhesion through integrin function but not expression. Furthermore, RhoA was activated upon stimulation with thrombin with subsequent cell contraction, decreased cell adhesion, and induced migration towards monocyte chemoattractant protein 1 (MCP-1; CCL2). Thus, it appears that thrombin stimulation plays a role in prostate cancer metastasis by decreasing cell adhesion to the extracellular matrix and positioning the cell in a "ready state" for migration in response to a chemotactic signal. Further exploration is needed to determine whether PAR1 activation affects other signaling pathways involved in prostate cancer.

摘要

晚期前列腺癌患者常表现出凝血系统激活增加。凝血级联反应的关键激活剂是丝氨酸蛋白酶凝血酶,它能够引发多种细胞反应。我们之前报道过凝血酶受体PAR1在前列腺癌中过度表达。为了进一步研究PAR1在前列腺癌转移中的作用,我们检测了凝血酶激活对PC-3前列腺癌细胞黏附和运动的影响。PAR1的激活诱导了动态细胞骨架重组,并降低了PC-3与I型胶原、IV型胶原和层粘连蛋白的结合(P<0.01),但对纤连蛋白无影响。通过流式细胞术评估,细胞表面整合素受体的表达没有变化。免疫荧光显微镜显示,PAR1刺激导致粘着斑重组,这表明PC-3细胞中PAR1的激活可能通过整合素功能而非表达来调节细胞黏附。此外,凝血酶刺激后RhoA被激活,随后细胞收缩、细胞黏附减少,并诱导细胞向单核细胞趋化蛋白1(MCP-1;CCL2)迁移。因此,凝血酶刺激似乎通过降低细胞与细胞外基质的黏附以及使细胞处于对趋化信号作出迁移反应的“准备状态”而在前列腺癌转移中发挥作用。需要进一步探索以确定PAR1激活是否影响参与前列腺癌的其他信号通路。

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