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

BACKGROUND: Gastric cancer cells frequently metastasise, partly because of their highly invasive nature. Transforming growth factor-beta (TGF-beta) receptor signalling is closely associated with the invasion of cancer cells. The aim of this study was to clarify the effect of a TGF-beta receptor (T beta R) 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 T beta R type I (T beta R-I) kinase inhibitor, Ki26894, inhibits the phosphorylation of Smad2 at an ATP-binding site of T beta R-I. We investigated the expression levels of T beta R and phospho-Smad2, and the effects of TGF-beta 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: T beta R-I, T beta R-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-beta 1 in scirrhous gastric cancer cells. Transforming growth factor-beta 1 upregulated the invasion, migration, and EMT ability of scirrhous gastric cancer cells. Transforming growth factor-beta 1 significantly upregulated the activity of RhoA and myosin phosphorylation, whereas TGF-beta 1 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-beta 1 or Ki26894 treatment. CONCLUSION: A T beta R-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. British Journal of Cancer (2010) 102, 844-851. doi: 10.1038/sj.bjc.6605561 www.bjcancer.com Published online 9 February 2010 (C) 2010 Cancer Research UK