Arsenic sulfide inhibits cell migration and invasion of gastric cancer in vitro and in vivo.
BACKGROUND
We previously showed that arsenic sulfide (As4S4) 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 As4S4 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 As4S4 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 As4S4 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
As4S4 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 As4S4. Moreover, the protease activities of MMP-2 and MMP-9 were suppressed by As4S4 in MGC803 cells. Meanwhile, As4S4 effectively suppressed the abilities of tumor growth and invasion in the xenograft tumor model. We found that As4S4 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.


CONCLUSIONS
As4S4 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.
Department of Oncology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
Lian
L
Zhang
Department of Oncology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
Sungkyoung
S
Kim
Department of Oncology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
Wenping
W
Ding
Department of Oncology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
Yingying
Y
Tong
Department of Oncology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
Xiuli
X
Zhang
Department of Oncology and Hematology, Kaiser Permanente Medical Center, Santa Clara, CA, USA.
Minggui
M
Pan
Department of Oncology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
Siyu
S
Chen
D000818:Animals; D015703:Antigens, CD; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001152:Arsenicals / Q000494:pharmacology*; D015820:Cadherins / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic; D015398:Signal Transduction / Q000187:drug effects; D016329:Sp1 Transcription Factor / Q000378:metabolism; D013274:Stomach Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013440:Sulfides / Q000494:pharmacology*; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000378:metabolism
D015703:Antigens, CD; D000970:Antineoplastic Agents; D001152:Arsenicals; C513384:CDH1 protein, human; C495270:CTNNB1 protein, human; D015820:Cadherins; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D016329:Sp1 Transcription Factor; C108209:SP1 protein, human; D013440:Sulfides; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D051176:beta Catenin; C045816:arsenic trisulfide; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9
As4S4; E-cadherin; MMPs; VEGF; realgar; xenograft