Arsenic Trioxide Suppressed Migration and Angiogenesis by Targeting FOXO3a in Gastric Cancer Cells

Arsenic trioxide (As(2)O(3)), a traditional remedy in Chinese medicine, has been used in acute promyelocytic leukemia (APL) research and clinical treatment. Previous studies have shown that As(2)O(3) exerts its potent antitumor effects in solid tumors by regulating cell proliferation and survival. The aim of this study was to investigate whether As(2)O(3) inhibited gastric cancer cell migration and angiogenesis by regulating FOXO3a expression. We found that As(2)O(3) reduced gastric cancer cell viability in a dose-dependent manner and also inhibited cell migration and angiogenesis in vitro. Western blotting and immunofluorescence showed that As(2)O(3) downregulated the levels of p-AKT, upregulated FOXO3a expression in the nucleus, and attenuated downstream Vascular endothelial growth factor (VEGF) and Matrix metallopeptidase 9 (MMP9) expression. Moreover, we demonstrated that knockdown of FOXO3a significantly reversed the inhibition of As(2)O(3) and promoted cell migration and angiogenesis in vitro. Further, As(2)O(3) significantly inhibited xenograft tumor growth and angiogenesis by upregulating FOXO3a expression in vivo. However, knockdown of FOXO3a attenuated the inhibitory effect of As(2)O(3) in xenograft tumors, and increased microvessel density (MVD) and VEGF expression. Our results demonstrated that As(2)O(3) inhibited migration and angiogenesis of gastric cancer cells by enhancing FOXO3a expression.