The roles of mitoferrin-2 in the process of arsenic trioxide-induced cell damage in human gliomas

BACKGROUND: Among glioma treatment strategies, arsenic trioxide (As(2)O(3)) has shown efficacy as a therapeutic agent against human gliomas. However, the exact antitumor mechanism of action of As(2)O(3) is still unclear. Mitochondria are considered to be the major source of intracellular reactive oxygen species (ROS), which are known to be associated with As(2)O(3)-induced cell damage. Therefore, we investigated whether mitoferrin-2, a mitochondrial iron uptake transporter, participates in As(2)O(3)-induced cell killing in human gliomas. METHODS: Human glioma cell lines were used to explore the mechanism of As(2)O(3)’s antitumor effects. First, expression of mitoferrin-2 was analyzed in glioma cells that were pretreated with As(2)O(3.) Changes in ROS production and apoptosis were assessed. Furthermore, cell viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). RESULTS: In the present study we found that As(2)O(3) induced ROS production and apoptosis in glioma cells. In addition, gene expression of mitoferrin-2, a mitochondrial iron uptake transporter, was increased 4 to 5 fold after exposure to As(2)O(3) (5 μM) for 48 hours. Furthermore, apoptosis and cytotoxicity induced by As(2)O(3) in glioma cells were decreased after silencing the mitoferrin-2 gene. CONCLUSIONS: Our findings indicated that mitoferrin-2 participates in mitochondrial ROS-dependent mechanisms underlying As(2)O(3)-mediated damage in glioma cells.