Role of nitric oxide on integrin expression and migration in human lung cancer cell

Abstract

Nitric oxide (NO), a highly reactive free radical gas involving in vascular control and inflammatory response, has influenced on cancer metastasis, but the understanding of its regulation on integrin, an important protein functioning in adhesion and motility, is still largely unknown. Alteration of integrin pattern has been shown to have a dramatic impact on cancer cell migratory activities as well as the survival during dissemination. This study has revealed that the human lung cancer cell lines (H460, H292 and H23) exposed to non-toxic concentrations of NO (0-50 μM) had higher level of integrin αv and β1, and such an increase of the specific integrins correlated with augmented ability of cells to motile. The known migratory proteins downstream of integrins including focal adhesion kinase (FAK), active RhoA (Rho-GTP), active cell division control 42(Cdc42-GTP) were found to be significantly activated in response to NO. Besides, this study observed the augmented motile morphology of NO-treated cells indicated by the dramatic increase of filopodia (actin protrusion) per cell. In terms of underlying mechanism, this study also found that NO-treated cells exhibited increased active protein kinase G (PKG), protein kinase B (AKT) and FAK. Using pharmacological approach, as AKT is downstream target of PKG, the results proved that integrin modulating effect of NO was mediated through PKG/AKT-dependent mechanism as the change in integrin as mentioned were completely diminished by AKT inhibitor, but not FAK inhibitor. These findings indicate a novel role of NO on integrin regulation and its importance in migratory cancer behavior.