Inhibition of STAT3 in gastric cancer: role of pantoprazole as SHP-1 inducer.

Abstract

BACKGROUND:

We investigated the inhibitory effect of pantoprazole on signal transducer and activator of transcription 3 (STAT3) activity and invasiveness of gastric adenocarcinoma cells, and the role of SH2-containing protein tyrosine phosphatase 1 (SHP-1) in mediating role.

METHODS:

We used AGS and MKN-28 cells because of reduced SHP-1 and preserved p-STAT3 expression. Western blot, wound closure assay, Matrigel invasion assay and 3-D culture invasion assay were performed. Pharmacologic inhibitor of SHP-1 and siRNA were used for validation of the role of SHP-1.

RESULTS:

We observed that pantoprazole at 40, 80, and 160 μg/ml upregulated SHP-1 and downregulated p-STAT3 expression in a dose-dependent manner in AGS and MKN-28 cells. Furthermore, pantoprazole significantly downregulated mesenchymal markers (Snail1 and vimentin), upregulated epithelial marker (E-cadherin), and inhibited migration and invasion of AGS and MKN-28 cells. To validate the role of SHP-1 in inhibition of STAT3 activity by pantoprazole in gastric cancer cells, we performed pharmacologic inhibition (pervanadate) or knockdown of SHP-1 before pantoprazole treatment, which significantly attenuated the suppression of p-STAT3 and anti-migration and invasion effect by pantoprazole in AGS cells. In xenograft tumor model, tumor volume was significantly reduced by intraperitoneal injection of pantoprazole, with upregulation of SHP-1 and downregulation of p-STAT3, which were attenuated by concomitant injection of pervanadate.

CONCLUSION:

Our data suggest that the inhibitory effect of pantoprazole on cellular migration and invasion might be through inducing SHP-1 in gastric cancer cells.

• Authors: Jin Sung Koh, Moon Kyung Joo, Jong-Jae Park, Hyo Soon Yoo, Byung Il Choi, Beom Jae Lee, Hoon Jai Chun, Sang Woo Lee
• Journal: Cell & bioscience (Cell Biosci) Vol. 8 Pg. 50 ( 2018) ISSN: 2045-3701 [Print] England
• PMID: 30202514 (Publication Type: Journal Article)