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Mitochondrial dysfunction promotes cell migration via reactive oxygen species-enhanced β5-integrin expression in
Wen-Yi Hung1, Kuo-Hung Huang, Chew-Wun Wu
1Department and Institute of Pharmacology, School of Medicine, National Yang-Ming University, and Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.
Background:
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.
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 β5-integrin expression. Clinicopathologic characteristics of β5-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 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.
General Significance:
These results support the role of mitochondrial dysfunction in GC progression.
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