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 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.
Rendon
Beatriz E
BE
Molecular Targets Program, J. G. Brown Cancer Center, University of Louisville, Louisville, Kentucky 40202, USA.
Roger
Thierry
T
Teneng
Ivo
I
Zhao
Ming
M
Al-Abed
Yousef
Y
Calandra
Thierry
T
Mitchell
Robert A
RA
D000230:Adenocarcinoma / Q000196:embryology* / Q000473:pathology*; D000256:Adenoviridae / Q000235:genetics; D051242:Caveolin 1 / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology*; D008263:Macrophage Migration-Inhibitory Factors / Q000502:physiology*; D021962:Membrane Microdomains / Q000378:metabolism; D008954:Models, Biological; D009154:Mutation; D009361:Neoplasm Invasiveness; D034741:RNA, Small Interfering / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D051242:Caveolin 1; D008263:Macrophage Migration-Inhibitory Factors; D034741:RNA, Small Interfering; D020742:rhoA GTP-Binding Protein