Stromal cell-derived factor-1 enhances motility and integrin up-regulation through CXCR4, ERK and NF-kappaB-dependent pathway in human lung cancer cells.
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.
Huang
Yi-Chia
YC
School of Cosmeceutics, College of Pharmacy, China Medical University, Taichung, Taiwan.
Hsiao
Yu-Chun
YC
Chen
Ying-Ju
YJ
Wei
Ying-Ying
YY
Lai
Tzu-Hsu
TH
Tang
Chih-Hsin
CH
D001483:Base Sequence; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D054377:Chemokine CXCL12 / Q000502:physiology*; D017931:DNA Primers; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D016023:Integrins / Q000502:physiology*; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation; D011480:Protease Inhibitors / Q000494:pharmacology; D034741:RNA, Small Interfering; D019718:Receptors, CXCR4 / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation / Q000502:physiology*
D054377:Chemokine CXCL12; D017931:DNA Primers; D016023:Integrins; D016328:NF-kappa B; D011480:Protease Inhibitors; D034741:RNA, Small Interfering; D019718:Receptors, CXCR4; D048049:Extracellular Signal-Regulated MAP Kinases