HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 283, Issue 5, 2822-2834, February 1, 2008

This Article Full Text Full Text (PDF) All Versions of this Article: 283/5/2822    most recent M704855200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Radjabi, A. R. Articles by Lengyel, E. Search for Related Content PubMed PubMed Citation Articles by Radjabi, A. R. Articles by Lengyel, E. Social Bookmarking                      What's this?

Thrombin Induces Tumor Invasion through the Induction and Association of Matrix Metalloproteinase-9 and β1-Integrin on the Cell Surface^*

A. Reza Radjabi¹, Kenjiro Sawada¹, Sujatha Jagadeeswaran, Alfred Eichbichler, Hilary A. Kenny, Anthony Montag^¶, Katharina Bruno^||, and Ernst Lengyel^**2

From the Department of Obstetrics and Gynecology/Section of Gynecologic Oncology, Center for Integrative Science, the Departments of ^¶Pathology and ^||Biochemistry and Molecular Biology, and the ^**Committee on Cancer Biology, University of Chicago, Chicago, Illinois 60637 and the Department of Orthopedic Surgery, Bogenhausen Medical Center, Bavaria, 81925 Munich, Germany

The procoagulatory serine protease, thrombin, is known to induce invasion and metastasis in various cancers, but the mechanisms by which it promotes tumorigenesis are poorly understood. Because the 92-kDa gelatinase (MMP-9) is a known mediator of tumor cell invasion, we sought to determine whether and how thrombin regulates MMP-9. The thrombin receptor, PAR-1, and MMP-9 are expressed in osteosarcomas, as determined by immunohistochemistry. Stimulation of U2-OS osteosarcoma cells with thrombin and a thrombin receptor-activating peptide induced pro-MMP-9 secretion as well as cell surface-associated pro-MMP-9 expression and proteolytic activity. This was paralleled by an increase in MMP-9 mRNA and MMP-9 promoter activity. Thrombin-induced invasion of U2-OS cells through Matrigel was mediated by the phosphatidylinositol 3-kinase signaling pathway and could be inhibited with an MMP-9 antibody. The stimulation of MMP-9 by thrombin was paralleled by an increase in β1-integrin mRNA and β1-integrin expression on the cell surface, which was also mediated by phosphatidylinositol 3-kinase and was required for invasion. Thrombin activation induced and co-localized both β1-integrin and pro-MMP-9 on the cell membrane, as evidenced by co-immunoprecipitation, confocal microscopy, and a protein binding assay. The thrombin-mediated association of these two proteins, as well as thrombin-mediated invasion of U2-OS cells, could be blocked with a cyclic peptide and with an antibody preventing binding of the MMP-9 hemopexin domain to β1-integrin. These results suggest that thrombin induces expression and association of β1-integrin with MMP-9 and that the cell surface localization of the protease by the integrin promotes tumor cell invasion.

Received for publication, June 13, 2007 , and in revised form, November 15, 2007.

^* This work was supported by the Ovarian Cancer Research Fund (Liz Tilberis Scholars Program) and NCI Grant R01 CA111882 from the National Institutes of Health (to E. L.). 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.

¹ Both authors contributed equally to the work.

² To whom correspondence should be addressed: MC 2050, 5841 South Maryland Ave., Chicago, IL 60637. Tel.: 773-702-6722; Fax: 773-702-5411; E-mail: elengyel{at}uchicago.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?