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Arsenic Trioxide Suppressed Migration and Angiogenesis by Targeting FOXO3a in Gastric Cancer Cells.
- Source :
-
International journal of molecular sciences [Int J Mol Sci] 2018 Nov 24; Vol. 19 (12). Date of Electronic Publication: 2018 Nov 24. - Publication Year :
- 2018
-
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.
- Subjects :
- Animals
Cell Line, Tumor
Cell Movement drug effects
Cell Proliferation drug effects
Cell Survival drug effects
Dose-Response Relationship, Drug
Forkhead Box Protein O3 antagonists & inhibitors
Forkhead Box Protein O3 metabolism
Human Umbilical Vein Endothelial Cells cytology
Human Umbilical Vein Endothelial Cells drug effects
Humans
Male
Matrix Metalloproteinase 9 genetics
Matrix Metalloproteinase 9 metabolism
Mice
Mice, Nude
Neovascularization, Pathologic genetics
Neovascularization, Pathologic metabolism
Neovascularization, Pathologic pathology
Proto-Oncogene Proteins c-akt genetics
Proto-Oncogene Proteins c-akt metabolism
RNA, Small Interfering genetics
RNA, Small Interfering metabolism
Signal Transduction
Stomach Neoplasms genetics
Stomach Neoplasms metabolism
Stomach Neoplasms pathology
Vascular Endothelial Growth Factor A genetics
Vascular Endothelial Growth Factor A metabolism
Xenograft Model Antitumor Assays
Antineoplastic Agents pharmacology
Arsenic Trioxide pharmacology
Forkhead Box Protein O3 genetics
Gene Expression Regulation, Neoplastic
Neovascularization, Pathologic drug therapy
Stomach Neoplasms drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1422-0067
- Volume :
- 19
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- International journal of molecular sciences
- Publication Type :
- Academic Journal
- Accession number :
- 30477221
- Full Text :
- https://doi.org/10.3390/ijms19123739