evaluation of drug resistance in the tamoxifen-treated mkn-45 gastric cancer cell line via the epithelial-mesenchymal transition signaling pathway

One of the major challenges in gastric cancer (gc) chemotherapy is the phenomenon of multi-drug resistance (mdr). the epithelial-mesenchymal transition (emt) and its key molecules, transforming growth factor-β (tgfβ) and smad2, play a central role in mdr occurrence.  tamoxifen (tam), a triphenylethylene derivative, can overcome mdr in human gastric cancers. the aim of this study was to investigate the effect of tam on 5-fu resistance of gc by suppressing the tgfβ1/smad2 signaling pathway and emt. the mkn-45 cell line was subjected to treatment with 5-fu, tam and a combination of both. the mtt assay was used to investigate the cytotoxic effects of 5-fu and tam, and the dna laddering technique was used to assess dna fragmentation and apoptosis. real-time rt-pcr examined the change in gene expression in emt-related genes (snai2, vim, tgfβ1 and smad2). the results of the present study indicated that not only tam treatment significantly decreased the ic50 of 5-fu (p≤0.05), but also the addition of tam to 5-fu induced apoptosis in the mkn-45 cell line. treatment with tam and 5-fu significantly inhibited tgfβ1 and tgfβ1-induced expression of emt markers (vim and snai2) in mkn-45 cells (p≤0.05). the reduction of tgfβ1 targets downstream of the smad2 signaling pathway reversed the process of emt and significantly increased the sensitivity of mkn-45 cells to 5-fu. the results of the present study suggested that reversal of emt-mediated mdr via the tgfβ1/smad signaling pathway using tam may be a potential new therapeutic strategy to overcome chemoresistance to 5-fu during gc chemotherapy.