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Phosphatidylinositol 3-kinase and NF-kappaB regulate motility of invasive MDA-MB-231 human breast cancer cells by the secretion of urokinase-type plasminogen activator

三三九九添加于 2015-11-24 15:17 | 1405 次阅读 | 0 个评论

作者
Sliva D, Rizzo MT, English D
摘要
Cell migration is a fundamental aspect of the neoplastic cell metastasis. Here, we show that phosphatidylinositol (PI) 3-kinase is constitutively active and controls cell motility of highly invasive breast cancer cells by the activation of transcription factor, NF-kappaB. The urokinase-type plasminogen activator (uPA) promoter contains an NF-kappaB binding site, and uPA expression in MDA-MB-231 cells is induced by the constitutively active NF-kappaB. Thus, motility was inhibited by overexpression of a dominant negative p85alpha regulatory subunit of PI 3-kinase (p85DN), as well as by pretreatment of cells with specific inhibitors of the p110 catalytic subunit of PI 3-kinase, wortmannin and LY294002. The involvement of gene transcription in cell motility was suggested because treatment with actinomycin D and cycloheximide, which inhibit transcription and new protein synthesis, respectively, abolished endogenous migration of MDA-MB-231 cells. Although wortmannin, Ly294002, or overexpression of p85DN did not significantly reduce DNA binding activity of NF-kappaB in nuclear extracts, wortmannin, Ly294002, and the overexpression of p85DN or IkappaBalpha inhibited constitutive activation of NF-kappaB in a reporter gene assay. Highly invasive MDA-MB-231 cells constitutively secreted uPA in amounts significantly higher than poorly invasive MCF-7 cells. Furthermore, inhibition of NF-kappaB markedly attenuated endogenous migration, and inhibition of PI 3-kinase and NF-kappaB reduced secretion of uPA. Our data suggest a link between constitutively active PI 3-kinase, NF-kappaB, and secretion of uPA, which is responsible for the migration of highly invasive breast cancer cells. Thus, constitutively active PI 3-kinase controls cell motility by the regulation of expression of uPA through the activation of NF-kappaB.
详细资料
- 关键词: Androstadienes/pharmacology; Breast Neoplasms/*pathology/*physiopathology; Cell Movement/drug effects/*physiology; Chloramphenicol O-Acetyltransferase/genetics; Chromones/pharmacology; DNA-Binding Proteins/genetics/metabolism; Enzyme Inhibitors/pharmacology; Female; Genes, Reporter; Humans; *I-kappa B Proteins; Morpholines/pharmacology; NF-kappa B/*metabolism; *Neoplasm Invasiveness; Phosphatidylinositol 3-Kinases/*metabolism; Plasmids; Recombinant Fusion Proteins/metabolism; Transfection; Tumor ...
- 文献种类: Journal Article
- 期刊名称: The Journal of Biological Chemistry
- 期刊缩写: J Biol Chem
- 期卷页: 2002年第277卷第5期 3150-3157页
- 地址: Cancer Research Laboratory, the Signal Transduction Laboratory, and the Experimental Cell Research Program, Methodist Research Institute, Clarian Health Partners Inc., Indianapolis, Indiana 46202, USA. dsliva@clarian.org
- ISBN: 0021-9258
学科领域生物医药 » 药学
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