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標題: Stromal Cell-Derived Factor-1/CXCR4 Enhanced Motility of Human Osteosarcoma Cells Involves MEK1/2, ERK and NF-kappa B-Dependent Pathways
作者: Huang, C.Y.
Lee, C.Y.
Chen, M.Y.
Yang, W.H.
Chen, Y.H.
Chang, C.H.
Hsu, H.C.
Fong, Y.C.
Tang, C.H.
關鍵字: lung-cancer cells;human chondrosarcoma cells;integrin up-regulation;signal-transduction;chemokine receptor;tumor-cells;alpha-v-beta-3;cxcr4;metastasis;expression
Project: Journal of Cellular Physiology
期刊/報告no:: Journal of Cellular Physiology, Volume 221, Issue 1, Page(s) 204-212.
Osteosarcoma is characterized by a high malignant and metastatic potential. The chemokine stromal-derived factor-1 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, and has been associated with metastasis of cancer cells. Here, we found that human osteosarcoma cell lines had significant expression of SDF-1 and CXCR4 (SDF-1 receptor). Treatment of osteosarcoma cells with SDF-1 alpha increased the migration and cell surface expression of alpha nu beta 3 integrin. CXCR4-neutralizing antibody, CXCR4 specific inhibitor (AMD3100) or small interfering RNA against CXCR4 inhibited the SDF-1 alpha-induced increase the migration and integrin expression of osteosarcoma cells. Pretreated of osteosarcoma cells with MAPK kinase (MEK) inhibitor PD98059 inhibited the SDF-1 alpha-mediated migration and integrin expression. Stimulation of cells with SDF-1 alpha increased the phosphorylation of MEK and extracellular signal-regulating kinase (ERK). In addition, NF-kappa B inhibitor (PDTC) or I kappa B protease inhibitor (TPCK) also inhibited SDF-1 alpha-mediated cell migration and integrin up-regulation. Stimulation of cells with SDF-1 alpha induced I kappa B kinase (IKK alpha/beta) phosphorylation, I kappa B phosphorylation, p65 Ser(536) phosphorylation, and kappa B-luciferase activity. Furthermore, the SDF-1 alpha-mediated increasing kappa B-luciferase activity was inhibited by AMD3100, PD98059, PDTC and TPCK or MEK 1, ERK2, IKK alpha and IKK beta mutants. Taken together, these results suggest that the SDF-1 alpha acts through CXCR4 to activate MEK and ERK, which in turn activates IKK alpha/beta and NF-kappa B, resulting in the activations of alpha nu beta 3 integrins and contributing the migration of human osteosarcoma cells. J. Cell. Physiol. 221: 204-212, 2009. (C) 2009 Wiley-Liss, Inc.
ISSN: 0021-9541
DOI: 10.1002/jcp.21846
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