BMP-2 Increases Migration of Human Chondrosarcoma Cells Via PI3K/Akt Pathway

Bone morphogenetic protein-2 (BMP-2), a member of transforming growth factor-beta superfamily, plays a crucial role in migration and metastasis of human cancer cells. Integrins are the major adhesive molecules in mammalian cells cancer cells (JJ012). Here we found that BMP-2 directed the migration and increased cell surface and mRNA expression of beta 1 integrin in human chondrosarcoma cancer cells (JJ012). Pretreated of JJ012 cells with phosphatidylinositol 3-kinase inhibitor (PI3K; Ly294002) or Akt inhibitor inhibited the BMP-2-mediated migration and integrin expression. BMP-2 increased the phosphorylation of p85 subunit of PI3K and serine 473 of Akt. In addition, NF-kappa B inhibitor (PDTC) or I kappa B protease inhibitor (TPCK) also inhibited BMP-2-mediated cells migration and integrin upregulation. Stimulation of JJ012 cells with BMP-2 induced I kappa B kinase (IKK alpha/beta) phosphorylation, I kappa B phosphorylation, p65 Ser(536) phosphorylation, and kappa B-luciferase activity. Furthermore, the BMP-2-mediated increasing of IKK alpha/beta phosphorylation, IKB phosphorylation, and p65 Ser(536) phosphorylation were inhibited by Ly294002 and Akt inhibitor. Co-transfection with p85 and Akt mutants also reduced the BMP-2-induced kappa B-luciferase activity. Taken together, these results suggest that the BMP-2 acts through PI3K/Akt, which in turn activates IKK alpha/beta and NF-kappa B, resulting in the activations of beta 1 integrin and contributing the migration of human chondrosarcoma cells.