Regulation of human lung adenocarcinoma cell migration and invasion by macrophage migration inhibitory factor

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 RNAmediated 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 thatMIFdepletion 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.