Journal
CANCER LETTERS
Volume 356, Issue 2, Pages 704-712Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2014.10.016
Keywords
Drug resistance; Invasiveness; Epithelial to mesenchymal transition; Pantoprazole
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Funding
- National Natural Science Foundation of China [81101814, 81272742, 81201908, 81472756, 81201909]
- Nanjing University State Key Laboratory of Pharmaceutical Biotechnology [KF-GN-201206]
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The effect of proton pump inhibitor (PPI) on cancer risk has received much attention recently. In this study, we investigated the mechanism underlying multidrug resistance and the effect of a PPI pantoprazole using an adriamycin-resistant gastric cancer cell model (SGC7901/ADR). Compared with the parental cell line, SGC7901/ADR cells showed reduced proliferation rate, but higher resistance to adriamycin under both anchorage-dependent and -independent conditions. Notably, SGC7901/ADR cells underwent epithelial to mesenchymal transition (EMT) and showed increased migrating and invading capabilities. At molecular level, SGC7901/ADR cells showed strong activation of Wnt/beta-catenin signaling pathway compared with parental sensitive cells. Interestingly, we found that a PPI pantoprazole can effectively reverse the aggressiveness and EMT marker expression of SGC7901/ADR cells. Furthermore, pantoprazole treatment resulted in a profound reduction of both total and phosphorylated forms of Akt and GSK-3 beta, which in turn suppressed the adriamycin-induced Wnt/beta-catenin signaling in SGC7901/ADR cells. Taken together, we demonstrate that the aggressive phenotype of adriamycin-resistant SGC7901/ADR cells is mediated by induction of EMT and activation of the canonical Wnt/beta-catenin signaling pathway. And for the first time, we show that it is possible to suppress the invasiveness of SGC7901/ADR cells by pantoprazole which targets the EMT and Akt/GSK-3 beta/beta-catenin signaling. (C) 2014 Elsevier Ireland Ltd. All rights reserved.
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