RANKL Increases Migration of Human Lung Cancer Cells Through Intercellular Adhesion Molecule-1 Up-Regulation

Invasion of distant tissues by tumor cells is the primary cause of therapeutic failure in the treatment of malignant lung cancer cells. Receptor activator of nuclear factor-kappa B ligand (RANKL) and its receptor, RANK, play a key role in osteoclastogenesis and tumor metastasis. Intercellular adhesion molecule-1 (1CAM-1, also called CD54), a member of the immunoglobulin supergene family, is an inducible surface glycoprotein that mediates adhesion-dependent cell-to-cell interactions. The effects of RANKL on cell migration and ICAM-1 expression in human lung cancer cells are largely unknown. We found that RANKL directed the migration and increased ICAM-1 expression in human lung cancer (A549) cells. Pretreatment of A549 cells with the MAPK kinase (MEK) inhibitor PD98059 or U0126 inhibited RANKL-mediated migration and ICAM-1 expression. Stimulation of cells with RANKL increased the phosphorylation of MEK and extracellular signal-regulating kinase (ERK). In addition, an NF-kappa B inhibitor (PDTC) and I kappa B protease inhibitor (TPCK) also inhibited RANKL-mediated cell migration and ICAM-1 upregulation. Taken together, these results suggest that the RANKL and RANK interaction acts through MEK/ERK, which in turn activates NF-kappa B, resulting in the activation of ICAM-I and contributing to the migration of human lung cancer cells. J. Cell. Biochem. 112: 933-941, 2011. (C) 2010 Wiley-Liss, Inc.