Stromal cell-derived factor-1 enhances motility and integrin up-regulation through CXCR4, ERK and NF-kappaB-dependent pathway in human lung cancer cells

Biochem Pharmacol. 2007 Dec 15;74(12):1702-12. doi: 10.1016/j.bcp.2007.08.025. Epub 2007 Aug 25.


The chemokine stromal-derived factor-1alpha (SDF-1alpha) and its receptor, CXCR4, play a crucial role in adhesion and migration of human cancer cells. Integrins are the major adhesive molecules in mammalian cells. Here we found that SDF-1alpha increased the migration and cell surface expression of beta1 or beta3 integrin in human lung cancer cells (A549 cells). CXCR4-neutralizing antibody, CXCR4 specific inhibitor (AMD3100) or small interfering RNA against CXCR4 inhibited the SDF-1alpha-induced increase in the migration of lung cancer cells. Stimulation of cells with SDF-1alpha caused an increase in extracellular signal regulated kinase (ERK) phosphorylation in a time-dependent manner. In addition, treatment of A549 cells with ERK inhibitor (PD98059), NF-kappaB inhibitor (PDTC) or IkappaB protease inhibitor (TPCK) inhibited SDF-1alpha-induced cells migration and integrins expression. Treatment of A549 cells with SDF-1alpha induced IkappaB kinase alpha/beta (IKK alpha/beta) phosphorylation, IkappaBalpha phosphorylation, IkappaBalpha degradation, p65 Ser(536) phosphorylation, and kappaB-luciferase activity. The SDF-1alpha-mediated increases in IKK alpha/beta phosphorylation, p65 Ser(536) phosphorylation, and kappaB-luciferase activity were inhibited by PD98059 and ERK2 mutant. Taken together, these results suggest that SDF-1alpha acts through CXCR4 to activate ERK, which in turn activates IKKalpha/beta and NF-kappaB, resulting in the activations of beta1 and beta3 integrins and contributing the migration of lung cancer cell.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Cell Line, Tumor
  • Cell Movement / physiology*
  • Chemokine CXCL12 / physiology*
  • DNA Primers
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Humans
  • Integrins / physiology*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology*
  • Lung Neoplasms / physiopathology
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism*
  • Phosphorylation
  • Protease Inhibitors / pharmacology
  • RNA, Small Interfering
  • Receptors, CXCR4 / metabolism*
  • Signal Transduction
  • Up-Regulation / physiology*


  • Chemokine CXCL12
  • DNA Primers
  • Integrins
  • NF-kappa B
  • Protease Inhibitors
  • RNA, Small Interfering
  • Receptors, CXCR4
  • Extracellular Signal-Regulated MAP Kinases