p38 mitogen-activated protein kinase regulates chemoresistance in human gastric cancer via epithelial mesenchymal transition

Gastric cancer is the most common cancer throughout the world. Acquired chemoresistance and epithelial mesenchymal transition (EMT) emerge as critical steps in the progression of gastric cancer. p38 mitogenactivated protein kinase (MAPK) signaling is involved in the anti-apoptotic and EMT process. Our current work aimed to evaluate the effects of p38 MAPK in adriamycin (ADM)-resistant human gastric cancer cells. Cell proliferation was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Real-time polymerase chain reaction (RT-PCR) and Western blot analysis were performed to detect the mRNA and protein expression levels. Compared with the parental cells, the p38 MAPK activation was remarkably increased in SGC7901/ADM and BGC823/ADM cells. Downregulation of p38 expression by p38 siRNA sensitized chemoresistant tumor cells to ADM administration. In addition, the EMT related markers E-cadherin or vimentin was up-regulated or down-regulated upon the inhibition of p38 MAPK in gastric cancer cells. Further studies identified the inhibition of p38 partially reversed the EMT changes found in this cell system, as illustrated by decreased gene expression of the EMT marker zinc finger E-box-binding homeobox 2 (ZEB2) protein and mRNA levels, a known EMT promoter, concomitant with increased E-cadherin protein. Taken together, our results demonstrated that downregulation of p38, which might be associated with the inactivation of the p38 MAPK signaling pathway, sensitizes gastric cancer cells to ADM via EMT, suggesting that p38 MAPK is a promising target for the design of targeted therapies for overcoming drug-resistant gastric cancer cells.