Abstract
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.
Keywords:
As2O3; FOXO3a; angiogenesis; gastric cancer; migration.
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology*
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Arsenic Trioxide / pharmacology*
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Cell Line, Tumor
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Cell Movement / drug effects
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Cell Proliferation / drug effects
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Cell Survival / drug effects
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Dose-Response Relationship, Drug
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Forkhead Box Protein O3 / antagonists & inhibitors
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Forkhead Box Protein O3 / genetics*
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Forkhead Box Protein O3 / metabolism
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Gene Expression Regulation, Neoplastic*
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Human Umbilical Vein Endothelial Cells / cytology
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Human Umbilical Vein Endothelial Cells / drug effects
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Humans
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Male
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Matrix Metalloproteinase 9 / genetics
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Matrix Metalloproteinase 9 / metabolism
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Mice
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Mice, Nude
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Neovascularization, Pathologic / drug therapy*
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Neovascularization, Pathologic / genetics
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Neovascularization, Pathologic / metabolism
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Neovascularization, Pathologic / pathology
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Signal Transduction
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Stomach Neoplasms / drug therapy*
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Stomach Neoplasms / genetics
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Stomach Neoplasms / metabolism
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Stomach Neoplasms / pathology
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Vascular Endothelial Growth Factor A / genetics
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Vascular Endothelial Growth Factor A / metabolism
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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FOXO3 protein, human
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Forkhead Box Protein O3
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RNA, Small Interfering
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VEGFA protein, human
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Vascular Endothelial Growth Factor A
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Proto-Oncogene Proteins c-akt
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MMP9 protein, human
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Matrix Metalloproteinase 9
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Arsenic Trioxide