BTG2 is a tumor suppressor gene. It is frequently downregulated in human cancer tissues, and its loss is associated with cancer cell metastasis, suggesting that the suppression of BTG2 plays a critical role in cancer cell migration and invasion. Here, we report that re-expression of BTG2 decreased cell migration and invasion in A549 and PC3 cancer cells. Furthermore, BTG2 expression was correlated with downregulation of focal adhesion kinase (FAK) Tyr576 and Tyr925 residues phosphorylation, while Tyr397 which is the autophosphorylation site was not influenced by BTG2 expression. c-Src phosphorylation which is the upstream of FAK was not influenced, whereas c-Src kinase activity was significantly decreased by BTG2 expression. BTG2 overexpression increased Src reduction state and inhibited reactive oxygen species (ROS) generation by being localized in mitochondria. Mitochondria-target BTG2 also inhibited cell migration via downregulation of Src-FAK signaling. In conclusion, our study reveals that BTG2 negatively regulated cancer cell migration by inhibiting Src activity through downregulation of ROS generation in mitochondria.

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