76 Background: Arsenic trioxide (ATO) is known to inhibit epithelial-mesenchymal transition (EMT) in hepatolocellular carcinoma and breast cancer cells, however, little has been reported in gastric cancer cells. In this study, we aimed to investigate the mechanism of ATO to inhibit signal transducer and activator of transcription 3 (STAT3) activity and EMT in gastric cancer cells. Methods: We performed wound closure assay and Matrigel invasion assay for functional studies of EMT, and western blot for measurement of protein markers using AGS gastric cancer cells. Results: Compared with control, 5 and 10 μM of ATO significantly inhibited cellular migration and inhibition in a dose-dependent manner. Furthermore, ATO significantly downregulated snail expression, a mesenchymal marker, and upregulated E-cadherin expression, an epithelial marker. We could observe that ATO induced SH2-containing protein tyrosine phosphatase 1 (SHP1), a non-receptor type protein tyrosine phosphatase, and subsequently downregulated phospho-STAT3 in a dose-dependent manner. To validate the molecular link between ATO and SHP1 to inhibit EMT in gastric cancer cell, we pre-treated 50 μM of pervanadate, a phosphatase inhibitor, before treatment of 10 μM ATO, and this significantly abolished anti-invasive effect by ATO in AGS cells. In xenograft tumor model, intraperitoneal injection of ATO significantly reduced the tumor volume and upregulated SHP-1 expression by immunohistochemistry stain compared with vehicle, which were reversed by ATO with pervanadate injection. Conclusions: Our findings suggest that ATO may show anti-EMT effects via induction of SHP1 and inhibition of STAT3 activity in gastric cancer cells.
Antitumorigenic effect of plumbagin by induction of SH2-containing protein tyrosine phosphatase 1 in human gastric cancer cells
