Inhibitory effect of a TGFΒ receptor type-I inhibitor, Ki26894, on invasiveness of scirrhous gastric cancer cells

Abstract

Background:Gastric cancer cells frequently metastasise, partly because of their highly invasive nature. Transforming growth factor-Β (TGF-Β) receptor signalling is closely associated with the invasion of cancer cells. The aim of this study was to clarify the effect of a TGF-Β receptor (TΒR) phosphorylation inhibitor on the invasiveness of gastric cancer cells.Methods:Four gastric cancer cell lines, including two scirrhous-type cell lines and two non-scirrhous-type cell lines, were used. A TΒR type I (TΒR-I) kinase inhibitor, Ki26894, inhibits the phosphorylation of Smad2 at an ATP-binding site of TΒR-I. We investigated the expression levels of TΒR and phospho-Smad2, and the effects of TGF-Β in the presence or absence of Ki26894 on Smad2 phosphorylation, invasion, migration, epithelial-to-mesenchymal transition (EMT), Ras homologue gene family member A (RhoA), ZO-2, myosin, and E-cadherin expression of gastric cancer cells.Results:TΒR-I, TΒR-II, and phospho-Smad2 expressions were found in scirrhous gastric cancer cells, but not in non-scirrhous gastric cancer cells. Ki26894 decreased Smad2 phosphorylation induced by TGF-Β1 in scirrhous gastric cancer cells. Transforming growth factor-Β1 upregulated the invasion, migration, and EMT ability of scirrhous gastric cancer cells. Transforming growth factor-Β1 significantly upregulated the activity of RhoA and myosin phosphorylation, whereas TGF-Β1 decreased ZO-2 and E-cadherin expression in scirrhous gastric cancer cells. Interestingly, Ki26894 inhibited these characteristics in scirrhous gastric cancer cells. In contrast, non-scirrhous gastric cancer cells were not affected by TGF-Β1 or Ki26894 treatment.Conclusion:A TΒR-I kinase inhibitor decreases the invasiveness and EMT of scirrhous gastric cancer cells. Ki26894 is therefore considered to be a promising therapeutic compound for the metastasis of scirrhous gastric carcinoma. © 2010 Cancer Research UK All rights reserved.