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J. Biol. Chem., Vol. 282, Issue 41, 29910-29918, October 12, 2007

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Regulation of Human Lung Adenocarcinoma Cell Migration and Invasion by Macrophage Migration Inhibitory Factor^*

Beatriz E. Rendon, Thierry Roger, Ivo Teneng, Ming Zhao, Yousef Al-Abed^¶, Thierry Calandra, and Robert A. Mitchell¹

From the Molecular Targets Program, J. G. Brown Cancer Center, and Department of Biochemistry & Molecular Biology, University of Louisville, Louisville, Kentucky 40202, the Division of Infectious Diseases, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland 1011, and the ^¶Laboratory of Medicinal Chemistry, The Feinstein Institute for Medical Research, Manhasset, New York 11030

Macrophage migration inhibitory factor (MIF) is expressed and secreted in response to mitogens and integrin-dependent cell adhesion. Once released, autocrine MIF promotes the activation of RhoA GTPase leading to cell cycle progression in rodent fibroblasts. We now report that small interfering RNA-mediated knockdown of MIF and MIF small molecule antagonism results in a greater than 90% loss of both the migratory and invasive potential of human lung adenocarcinoma cells. Correlating with these phenotypes is a substantial reduction in steady state as well as serum-induced effector binding activity of the Rho GTPase family member, Rac1, in MIF-deficient cells. Conversely, MIF overexpression by adenovirus in human lung adenocarcinoma cells induces a dramatic enhancement of cell migration, and co-expression of a dominant interfering mutant of Rac1 (Rac1^N17) completely abrogates this effect. Finally, our results indicate that MIF depletion results in defective partitioning of Rac1 to caveolin-containing membrane microdomains, raising the possibility that MIF promotes Rac1 activity and subsequent tumor cell motility through lipid raft stabilization.

Received for publication, June 13, 2007 , and in revised form, August 20, 2007.

^* This work was supported by grants from the Kentucky Lung Cancer Research Program and Philip Morris USA. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ To whom correspondence should be addressed: University of Louisville, Delia Baxter Research Bldg., Suite 204B, 580 S. Preston St., Louisville, KY 40202. Tel.: 502-852-7698; Fax: 502-852-5679; E-mail: robert.mitchell{at}louisville.edu.

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