Arsenic sulfide inhibits cell migration and invasion of gastric cancer in vitro and in vivo

Abstract

Background

We previously showed that arsenic sulfide (As ₄S ₄) induced cell cycle arrest and apoptosis in several human solid tumor cell lines, including those of gastric cancer. In this study, we investigated the effect of As ₄S ₄ on the migration and invasion of gastric cancer cells both in vitro and in vivo.

Methods

The human gastric cancer cell lines AGS and MGC803 were selected as in vitro models. Wound-healing migration assay and Transwell invasion assay were carried out to determine the effects of As ₄S ₄ on cell migration and invasion. The expressions of E-cadherin, β-catenin, Sp1, KLF4, and VEGF were measured by Western blotting analysis. The activities of matrix metalloproteinase (MMP)-2 and MMP-9 in MGC803 cells were demonstrated by zymography assay. A mouse xenograft model was established by inoculation with MGC803 cells, then intraperitoneal injected with As ₄S ₄ for 3 weeks and monitored for body weight and tumor changes. Finally, the inhibition rate of tumor growth was calculated, and the expression of proteins and genes associated with tumor invasion and metastasis in tumor tissues were measured by immunohistochemistry, Western blotting, and real-time polymerase chain reaction assay.

Results

As ₄S ₄ significantly inhibited the migration and invasion of gastric cancer cell lines. The expression of E-cadherin and KLF4 was upregulated, while the expressions of β-catenin, VEGF, and Sp1 were downregulated following treatment with As ₄S ₄. Moreover, the protease activities of MMP-2 and MMP-9 were suppressed by As ₄S ₄ in MGC803 cells. Meanwhile, As ₄S ₄ effectively suppressed the abilities of tumor growth and invasion in the xenograft tumor model. We found that As ₄S ₄ upregulated the expression of E-cadherin and downregulated the expression of β-catenin, Sp1, VEGF, and CD34 in mouse tumor tissues, consistent with the results in vitro.

Conclusion

As ₄S ₄ inhibited the migration and invasion of gastric cancer cells by blocking tumor cell adhesion, decreasing the ability of tumor cells to destroy the basement membrane, and therefore suppressing their angiogenesis.