Mitochondrial dysfunction promotes cell migration via reactive oxygen species-enhanced β5-integrin expression in human gastric cancer SC-M1 cells

Background: Mitochondria( dysfunction has been shown to promote cancer cell migration. However, molecular mechanism by which mitochondrial dysfunction enhances gastric cancer (GC) cell migration remains unclear. Methods: Mitochondria specific inhibitors, oligomycin and antimycin A, were used to induce mitochondrial dysfunction and to enhance cell migration of human gastric cancer SC-M1 cells. Antioxidant N-acetylcysteine (NAC) was used for evaluating the effect of reactive oxygen species (ROS). Protein expressions of epithelial-to-mesenchymal transition (EMT) markers and the cell-extracellular matrix (ECM) adhesion molecules, the integrin family, were analyzed. A migratory subpopulation of SC-M1 cells (SC-M1-3rd) was selected using a transwell assay for examining the association of mitochondrial bioenergetic function, intracellular ROS content and beta 5-integrin expression. Clinicopathologic characteristics of beta 5-integrin expression were analyzed in GC specimens by immunohistochemical staining. Results: Treatments with mitochondrial inhibitors elevated mitochondria-generated ROS and cell migration of SC-M1 cells. The protein expression of beta 5-integrin and cell surface expression of alpha v beta 5-integrin were upregulated, and which were suppressed by NAC. Pretreatments with NAC and anti-alpha v beta 5-integrin neutralizing antibody respectively prevented the mitochondrial dysfunction-induced cell migration. The selected migratory SC-M1-3rd cells showed impaired mitochondrial function, higher mitochondria-generated ROS, and increased beta 5-integrin expression. The migration ability was also repressed by anti-av beta 5-integrin neutralizing antibody. In clinical specimens, GCs with higher beta 5-integrin protein expression had more aggressive behavior. In conclusion, mitochondrial dysfunction may lead to GC progression by enhancing migration through mitochondria-generated ROS mediated beta 5-integrin expression. General significance: These results support the role of mitochondrial dysfunction in GC progression. (C) 2012 Elsevier B.V. All rights reserved.