Cisplatin at Sub-toxic Levels Mediates Integrin Switch in Lung Cancer Cells

Background: Resistance to chemotherapeutic agents, as well as enhanced metastasis, have been frequently reported in lung cancer. Materials and Methods: Cytotoxicity and proliferative effects of cisplatin on H460 lung cancer cells were evaluated by the MTT assay. Migration capacity was evaluated by the wound healing assay. The number of filopodia per cell were detected by rhodamine-phalloidin staining assay. The changes of protein levels of integrins, and migration-related proteins in response to cisplatin at sub-toxic concentrations were determined by western blotting. Results: Herein we demonstrate for the first time that exposure to low concentrations of cisplatin results in increase of cell motility with the alteration of integrin expression. Cisplatin-treated cells exhibited a significant increase in the number of filopodia per cell in correlation with enhanced migration. Migration regulatory proteins, namely activated forms of focal-adhesion kinase (FAK) and ATP-dependent tyrosine kinase (AKT), were found to significantly be up-regulated in cisplatin-treated cells in comparison to those of the non-treated control. Active Rho A-GTP and Rac-GTP were found to be increased in accordance with activation of FAK/AKT signals. Furthermore, we found that such migration enhancement may be in part due to the integrin switch mediated by cisplatin treatment. Cisplatin induced a dramatic alteration in the integrin expression pattern by up-regulating integrin alpha(4), alpha(v), beta(1), and beta(5) which were previously reported to increase cell motility, while it had no effect on integrin alpha(5), and beta(3). Conclusion: As the integrin switch is a hallmark of highly aggressive cancer, these findings may provide insights for better understanding of cancer cell adaptation after exposure to cisplatin.