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

• Published in: British journal of cancer Vol. 102; no. 5; pp. 844 - 851
• Main Authors: Shinto, O, Yashiro, M, Kawajiri, H, Shimizu, K, Shimizu, T, Miwa, A, Hirakawa, K
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02.03.2010; Nature Publishing Group
• Subjects: 631/45/127/1219; 631/80/84/2176; 631/92/609; 692/699/67/1504/1829; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Drug Resistance; Epidemiology; Gastroenterology. Liver. Pancreas. Abdomen; Medical sciences; Molecular Medicine; Oncology; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Translational Therapeutics; Tumors; phosphorylation inhibitor; Smad2; TGF; scirrhous gastric cancer; epithelial-to-mesenchymal transition; Phosphorylation; Smad protein; Transforming growth factor β; Malignant tumor; Mesenchymal cell; Metastasis; Stomach cancer; Cancerology; Digestive diseases; TGF-β; Inhibitor; Tumor cell; Cancer; Gastric disease; Biological receptor
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/sj.bjc.6605561

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 (T β 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 β R type I (T β R-I) kinase inhibitor, Ki26894, inhibits the phosphorylation of Smad2 at an ATP-binding site of T β R-I. We investigated the expression levels of T β R 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: T β R-I, T β 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- β 1 in scirrhous gastric cancer cells. Transforming growth factor- β 1 upregulated the invasion, migration, and EMT ability of scirrhous gastric cancer cells. Transforming growth factor- β 1 significantly upregulated the activity of RhoA and myosin phosphorylation, whereas TGF- β 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- β 1 or Ki26894 treatment. Conclusion: A T β 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.