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Originally published In Press as doi:10.1074/jbc.M109579200 on October 31, 2001

J. Biol. Chem., Vol. 277, Issue 5, 3150-3157, February 1, 2002
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Phosphatidylinositol 3-Kinase and NF-kappa B Regulate Motility of Invasive MDA-MB-231 Human Breast Cancer Cells by the Secretion of Urokinase-type Plasminogen Activator*

Daniel SlivaDagger §, Maria T. Rizzo, and Denis English||**

From the Dagger  Cancer Research Laboratory, the  Signal Transduction Laboratory, and the || Experimental Cell Research Program, Methodist Research Institute, Clarian Health Partners Inc., Indianapolis, Indiana 46202 and the ** School of Allied Health Sciences, Indiana University School of Medicine, Indianapolis, Indiana 46202

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-kappa B. The urokinase-type plasminogen activator (uPA) promoter contains an NF-kappa B binding site, and uPA expression in MDA-MB-231 cells is induced by the constitutively active NF-kappa B. 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-kappa B in nuclear extracts, wortmannin, Ly294002, and the overexpression of p85DN or Ikappa Balpha inhibited constitutive activation of NF-kappa B 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-kappa B markedly attenuated endogenous migration, and inhibition of PI 3-kinase and NF-kappa B reduced secretion of uPA. Our data suggest a link between constitutively active PI 3-kinase, NF-kappa B, 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-kappa B.

* This work was supported by National Institutes of Health Grants RO1 HL 61751 and PO1 HL 58064 and a Phi Beta Psi Sorority grant (to D. E.), grants from the Methodist Cancer Center (to D. E. and D. S.), and grants from Methodist Heart Institute (to D. S. and M. T. R.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ To whom correspondence should be addressed: Cancer Research Laboratory, Methodist Research Inst., 1633 N. Capitol Ave., MT 350, Indianapolis, IN 46202. Tel.: 317-962-5731; Fax: 317-962-7468; E-mail: dsliva@clarian.org.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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