TGF-β1 increases motility and αvβ3 integrin up-regulation via PI3K, Akt and NF-κB-dependent pathway in human chondrosarcoma cells

Abstract

Transforming growth factor-β1 (TGF-β1) plays an essential role in tumor progression and metastasis. Integrins are the major adhesive molecules in mammalian cells. Here we found that TGF-β1 increased the migration and cell surface expression of αvβ3 integrin in human chondrosarcoma cells (JJ012 cells). Phosphatidylinositol 3-kinase inhibitor (PI3K; Ly294002) or Akt inhibitor inhibited the TGF-β1-induced increase the migration of chondrosarcoma cells. TGF-β1 stimulation increased the phosphorylation of p85 subunit of PI3K, and serine 473 of Akt. In addition, treatment of JJ102 cells with NF-κB inhibitor (PDTC) or IκB protease inhibitor (TPCK) inhibited TGF-β1-induced cells migration and integrins expression. Treatment of JJ012 cells with TGF-β1-induced IκB kinase α/β (IKKα/β) phosphorylation, IκBα phosphorylation, p65 Ser536 phosphorylation, and κB-luciferase activity. The TGF-β1-mediated increases in IKKα/β phosphorylation and p65 Ser536 phosphorylation were inhibited by Ly294002 and Akt inhibitor. Cotransfection with p85 and Akt mutants also reduced the TGF-β1-induced κB-luciferase activity. Taken together, these results suggest that the TGF-β1 acts through PI3K/Akt, which in turn activates IKKα/β and NF-κB, resulting in the activations of αvβ3 integrins and contributing the migration of chondrosarcoma cells.