Mitochondrial dysfunction promotes cell migration via reactive oxygen species-enhanced β5-integrin expression in human gastric cancer SC-M1 cells.
Mitochondrial dysfunction has been shown to promote cancer cell migration. However, molecular mechanism by which mitochondrial dysfunction enhances gastric cancer (GC) cell migration remains unclear. 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 β5-integrin expression. Clinicopathologic characteristics of β5-integrin expression were analyzed in GC specimens by immunohistochemical staining. Treatments with mitochondrial inhibitors elevated mitochondria-generated ROS and cell migration of SC-M1 cells. The protein expression of β5-integrin and cell surface expression of αvβ5-integrin were upregulated, and which were suppressed by NAC. Pretreatments with NAC and anti-αvβ5-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 β5-integrin expression. The migration ability was also repressed by anti-αvβ5-integrin neutralizing antibody. In clinical specimens, GCs with higher β5-integrin protein expression had more aggressive behavior. In conclusion, mitochondrial dysfunction may lead to GC progression by enhancing migration through mitochondria-generated ROS mediated β5-integrin expression. These results support the role of mitochondrial dysfunction in GC progression.