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

The chemokine stromal-derived factor-1α (SDF-1α) 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-1α increased the migration and cell surface expression of β1 or β3 integrin in human lung cancer cells (A549 cells). CXCR4-neutralizing antibody, CXCR4 specific inhibitor (AMD3100) or small interfering RNA against CXCR4 inhibited the SDF-1α-induced increase in the migration of lung cancer cells. Stimulation of cells with SDF-1α 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-κB inhibitor (PDTC) or IκB protease inhibitor (TPCK) inhibited SDF-1α-induced cells migration and integrins expression. Treatment of A549 cells with SDF-1α induced IκB kinase α/β (IKK α/β) phosphorylation, IκBα phosphorylation, IκBα degradation, p65 Ser536 phosphorylation, and κB-luciferase activity. The SDF-1α-mediated increases in IKK α/β phosphorylation, p65 Ser536 phosphorylation, and κB-luciferase activity were inhibited by PD98059 and ERK2 mutant. Taken together, these results suggest that SDF-1α acts through CXCR4 to activate ERK, which in turn activates IKKα/β and NF-κB, resulting in the activations of β1 and β3 integrins and contributing the migration of lung cancer cell.