CTGF Enhances Migration and MMP-13 Up-Regulation Via αvβ3 Integrin, FAK, ERK, and NF-κB-Dependent Pathway in Human Chondrosarcoma Cells

Tumor malignancy is associated with several features such as proliferation ability and frequency of metastasis. Connective tissue growth factor (CTGF), a secreted protein that binds to integrins, modulates the invasive behavior of certain human cancer cells. However, the effect of CTGF on migration activity in human chondrosarcoma cells is mostly unknown. Here we found that CTGF increased the migration and expression of matrix metalloproteinase (MMP)-13 in human chondrosarcoma cells (JJ012 cells). RGD peptide, alpha v beta 3 monoclonal antibody (mAb) and MAPK kinase (MEK) inhibitors (PD98059 and U0126) but not RAD peptide inhibited the CTGF-induced increase of the migration and MMP-13 up-regulation of chondrosarcoma cells. CTGF stimulation increased the phosphorylation of focal adhesion kinase (FAK) and extracellular signal-regulated kinase (ERK). In addition, treatment of JJ012 cells with NF-kappa B inhibitor (PDTC) or I kappa B protease inhibitor (TPCK) inhibited CTGF-induced cell migration and MMP-13 up-regulation. Stimulation of JJ012 cells with CTGF also induced I kappa B kinase alpha/beta (IKK alpha/beta) phosphorylation, I kappa B alpha phosphorylation, p65 Ser(536) phosphorylation, and kappa B-luciferase activity. The CTGF-mediated increases in kappa B-luciferase activities were inhibited by RGD, PD98059, U0126 or FAK, and ERK2 mutant. Taken together, our results indicated that CTGF enhances the migration of chondrosarcoma cells by increasing MMP-13 expression through the alpha v beta 3 integrin, FAK, ERK, and NF-kappa B signal transduction pathway. J. Cell. Biochetn. 107: 345-356, 2009. (C) 2009 Wiley-Liss, Inc.