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

Robert A. Mitchell,Thierry Calandra,Yousef Al-Abed,Ming Zhao,Beatriz E. Rendon,Ivo Teneng,Thierry Roger

doi:10.1074/jbc.m704898200

Abstract

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.

Highlights

The acquisition of migratory and invasive properties by tumor cells is a central and often fatal step in neoplastic disease progression
Subsequent studies by the same group demonstrated that the requirement for cell adhesion in Rac-dependent p21-activated kinase (PAK) activation was due to the stabilization of caveolin-containing, cholesterol-enriched membrane microdomains and that these “lipid rafts” are necessary for Rac-GTP-mediated PAK activation [10, 11]
In addition to the discovery that MIF participates in growth factor signaling to mitogen-activated protein (MAP) kinase, later studies revealed a critical role for MIF in the modulation of adhesion-dependent activation of MAP kinase, in a sustained fashion [26]

Summary

Introduction

The acquisition of migratory and invasive properties by tumor cells is a central and often fatal step in neoplastic disease progression. Silencing or Inhibition of MIF Results in a Loss of Cell Adhesion and Invasive Potential in Human Lung Adenocarcinoma— Because integrin-dependent binding to extracellular matrices is necessary for actin reorganization and subsequent motility, we evaluated whether siRNA-mediated depletion of MIF influenced NSCLC cell adhesion and spreading on collagen.

Results

Conclusion