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-l alpha (SDF-1 alpha) 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-1 alpha increased the migration and cell surface expression of beta 1 or beta 3 integrin in human lung cancer cells (A549 cells). CXCR4-neutralizing antibody, CXCR4 specific inhibitor (AMD3100) or small interfering RNA against CXCR4 inhibited the SDIF-1 alpha-induced increase in the migration of lung cancer cells. Stimulation of cells with SDF-1 alpha 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-kappa B inhibitor (PDTC) Or I kappa B protease inhibitor (TPCK) inhibited SDF-1 alpha-induced cells migration and integrins expression. Treatment of A549 cells with SDF-1 alpha induced I kappa B kinase alpha/beta (IKK alpha/beta) phosphorylation, I kappa B alpha phosphorylation, I kappa B alpha degradation, p65 Ser(536) phosphorylation, and kappa B-luciferase activity. The SDF-1 alpha-mediated increases in IKK alpha/beta phosphorylation, p65 Ser(536) phosphorylation, and kappa B-luciferase activity were inhibited by PD98059 and ERK2 mutant. Taken together, these results suggest that SDF-1 alpha acts through CXCR4 to activate ERK, which in turn activates IKK alpha/beta and NF-kappa B, resulting in the activations of beta 1 and beta 3 integrins and contributing the migration of lung cancer cell. (c) 2007 Elsevier Inc. All rights reserved.