RANKL increases migration of human lung cancer cells through intercellular adhesion molecule-1 up-regulation

J Cell Biochem. 2011 Mar;112(3):933-41. doi: 10.1002/jcb.23009.


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-κB ligand (RANKL) and its receptor, RANK, play a key role in osteoclastogenesis and tumor metastasis. Intercellular adhesion molecule-1 (ICAM-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-κB inhibitor (PDTC) and IκB protease inhibitor (TPCK) also inhibited RANKL-mediated cell migration and ICAM-1 up-regulation. Taken together, these results suggest that the RANKL and RANK interaction acts through MEK/ERK, which in turn activates NF-κB, resulting in the activation of ICAM-1 and contributing to the migration of human lung cancer cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cell Movement
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Genes, Reporter
  • Humans
  • Intercellular Adhesion Molecule-1 / biosynthesis*
  • Intercellular Adhesion Molecule-1 / genetics
  • Luciferases / metabolism
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology*
  • MAP Kinase Kinase 1 / metabolism
  • MAP Kinase Kinase 2 / metabolism
  • NF-kappa B / metabolism
  • Phosphorylation
  • RANK Ligand / genetics
  • RANK Ligand / pharmacology
  • RANK Ligand / physiology*
  • RNA Interference
  • Signal Transduction
  • Up-Regulation


  • NF-kappa B
  • RANK Ligand
  • TNFSF11 protein, human
  • Intercellular Adhesion Molecule-1
  • Luciferases
  • MAP2K2 protein, human
  • Extracellular Signal-Regulated MAP Kinases
  • MAP Kinase Kinase 1
  • MAP Kinase Kinase 2
  • MAP2K1 protein, human