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

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.

The Role of Forkhead Box Proteins in Acute Myeloid Leukemia

“…Arsenic trioxide in combination with ATRA is currently considered the standard of care for adults with low-to-intermediate-risk APL, with a complete remission rate near to 100% [54]. Interestingly, Zhang et al have recently shown that ATO treatment of gastric cancer cells induced the upregulation of FOXO3A expression in the nucleus and that FOXO3A knockdown attenuated the effect of ATO treatment in gastric cancer cells and in mouse models [55]. Moreover, they also demonstrate that ATO-related nuclear upregulation of active FOXO3A is the result of its phosphorylation via the aforementioned AKT pathway, leading to inhibition of cell migration.…”

Evaluation of the target genes of arsenic trioxide in pancreatic cancer by bioinformatics analysis

“…The antitumor properties of ATO have been identified in a number of tumors (10–14). ATO has also been shown to inhibit the viability of pancreatic cancer stem cells in vitro and in vivo (38).…”

“…Combined treatment with retinoic acid (RA) and ATO has been demonstrated to be curative for the majority of patients with APL (7–9). Furthermore, an increasing number of studies have proven the anti-carcinogenic properties of ATO in different tumors, including in gastric cancer (10), lymphoma (11), bladder cancer (12), head and neck cancer (13), and ovarian cancer (14). Although it has been reported that ATO may inhibit the progression of pancreatic cancer (15), the potential targets and molecular mechanisms of action of ATO remain unclear.…”

Role of FOXO Transcription Factors in Cancer Metabolism and Angiogenesis

“…FOXO3 suppresses VEGF expression in breast cancer, and a cDNA microarray study in a colon carcinoma cell line provided evidence that it can repress the expression of Myc target genes [ 43 , 153 ]. Accordingly, the suppressive effect of the traditional Chinese remedy arsenic trioxide in gastric cancer cell migration and angiogenesis was reported to depend on the enhancement of nuclear FOXO3 expression and the attenuation of VEGF and MMP9 [ 154 ]. Paradoxically, the nuclear localization of FOXO3 was found to promote cell growth and tumor angiogenesis in neuroblastoma, and FOXO1 was shown to promote the transcription of VEGF-C in a prostate cancer cell line [ 155 , 156 ].…”