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

• Published in: International journal of molecular sciences Vol. 19; no. 12; p. 3739
• Main Authors: Zhang, Lin, Liu, Lei, Zhan, Shining, Chen, Lili, Wang, Yueyuan, Zhang, Yujie, Du, Jun, Wu, Yongping, Gu, Luo
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 24-11-2018; MDPI
• Subjects: Acute promyeloid leukemia; AKT protein; Angiogenesis; Antitumor activity; Apoptosis; Arsenic; Arsenic trioxide; As2O3; Breast cancer; Cell adhesion & migration; Cell cycle; Cell growth; Cell proliferation; Cell viability; FOXO3 protein; FOXO3a; Gastric cancer; Gelatinase B; Growth factors; Immunofluorescence; Leukemia; Lung cancer; Matrix metalloproteinases; Medical prognosis; Metalloproteinase; Metastasis; migration; Motility; Ovarian cancer; Promyeloid leukemia; Prostate cancer; Proteins; Solid tumors; Transcription factors; Tumors; Vascular endothelial growth factor; Western blotting; Wound healing; Xenografts; Xenotransplantation; migration; FOXO3a; gastric cancer; As2O3; angiogenesis
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms19123739

Arsenic trioxide (As₂O₃), a traditional remedy in Chinese medicine, has been used in acute promyelocytic leukemia (APL) research and clinical treatment. Previous studies have shown that As₂O₃ exerts its potent antitumor effects in solid tumors by regulating cell proliferation and survival. The aim of this study was to investigate whether As₂O₃ inhibited gastric cancer cell migration and angiogenesis by regulating FOXO3a expression. We found that As₂O₃ 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 As₂O₃ 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 As₂O₃ and promoted cell migration and angiogenesis in vitro. Further, As₂O₃ significantly inhibited xenograft tumor growth and angiogenesis by upregulating FOXO3a expression in vivo. However, knockdown of FOXO3a attenuated the inhibitory effect of As₂O₃ in xenograft tumors, and increased microvessel density (MVD) and VEGF expression. Our results demonstrated that As₂O₃ inhibited migration and angiogenesis of gastric cancer cells by enhancing FOXO3a expression.