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J. Biol. Chem., Vol. 280, Issue 11, 10564-10571, March 18, 2005

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Signaling Mechanisms Responsible for Lysophosphatidic Acid-induced Urokinase Plasminogen Activator Expression in Ovarian Cancer Cells^*

Hongbin Li, Xiaoqin Ye, Chitladda Mahanivong, Dafang Bian, Jerold Chun, and Shuang Huang¶

From the Department of Immunology and Molecular Biology, The Scripps Research Institute, La Jolla, California 92037

Lysophosphatidic acid (LPA) enhances urokinase plasminogen activator (uPA) expression in ovarian cancer cells; however, the molecular mechanisms responsible for this event have not been investigated. In this study, we used the invasive ovarian cancer SK-OV-3 cell line to explore the signaling molecules and pathways essential for LPA-induced uPA up-regulation. With the aid of specific inhibitors and dominant negative forms of signaling molecules, we determined that the G_i-associated pathway mediates this LPA-induced event. Moreover, constitutively active H-Ras and Raf-1-activating H-Ras mutant enhance uPA expression, whereas dominant negative H-Ras and Raf-1 block LPA-induced uPA up-regulation, suggesting that the Ras-Raf pathway works downstream of G_i to mediate this LPA-induced process. Surprisingly, dominant negative MEK1 or Erk2 displays only marginal inhibitory effect on LPA-induced uPA up-regulation, suggesting that a signaling pathway distinct from Raf-MEK1/2-Erk is the prominent pathway responsible for this process. In this report, we demonstrate that LPA activates NF-B in a Ras-Raf-dependent manner and that blocking NF-B activation with either non-phosphorylable IB or dominant negative IB kinase abolished LPA-induced uPA up-regulation and uPA promoter activation. Furthermore, introducing mutations to knock out the NF-B binding site of the uPA promoter results in over 80% reduction in LPA-induced uPA promoter activation, whereas this activity is largely intact with the promoter containing mutations in the AP1 binding sites. Thus these results suggest that the G_i-Ras-Raf-NF-B signaling cascade is responsible for LPA-induced uPA up-regulation in ovarian cancer cells.

Received for publication, October 27, 2004 , and in revised form, January 12, 2005.

^* This work was supported by the National Institute of Health Grant R01 CA93926 and the Department of Army Breast Cancer Research Program Grant DAMD 17-02-0561. This is paper IMM-16982 from The Scripps Research Institute. The costs of publication of this article were defrayed in part by the payment of page charges. This 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: Dept of Immunology, IMM-19, The Scripps Research Inst., 10550 N. Torrey Pines Rd., La Jolla, CA 92037. Tel.: 858-784-9211; Fax: 858-784-8472; E-mail: shuang{at}scripps.edu.

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