Osteopontin increases lung cancer cells migration via activation of the αvβ3 integrin/FAK/Akt and NF-κB-dependent pathway

Tumor malignancy is associated with several features such as proliferation ability and frequency of metastasis. Osteopontin (OPN), which is abundantly expressed in bone matrix, is involved in cell adhesion, migration, invasion and cell proliferation via interaction with its receptor, αvβ3 integrin. However, the effect of OPN on migration activity in human lung cancer cells is mostly unknown. Here we found that OPN increased the migration via activation of αvβ3 integrin in human lung cancer cells (A549 cells). Phosphatidylinositol 3-kinase inhibitor (PI3K; Ly294002), Akt inhibitor or ERK inhibitor (PD98059) inhibited the OPN-induced increase in the migration of lung cancer cells. OPN stimulation increased the phosphorylation of focal adhesion kinase (FAK), p85 subunit of PI3K, serine 473 of Akt and ERK. In addition, treatment of A549 cells with NF-κB inhibitor (PDTC) or IκB protease inhibitor (TPCK) inhibited OPN-induced migration of lung cancer cells. Stimulation of A549 cells with OPN also induced IκB kinase α/β (IKK α/β) phosphorylation, IκBα phosphorylation, p65 Ser536 phosphorylation, and κB-luciferase activity. The OPN-mediated increases in IKK α/β, IκBα and p65 Ser536 phosphorylation were inhibited by Ly294002, Akt inhibitor and PD98059. Co-transfection with FAK, p85, Akt and ERK mutants also reduced the OPN-induced κB-luciferase activity. Taken together, these results suggest that OPN acts through αvβ3 integrin, which in turn activates the FAK, PI3K, Akt, ERK and NF-κB pathways, contributing to the migration of lung cancer cells.