Inhibitory effect of a TGFbeta receptor type-I inhibitor, Ki26894, on invasiveness of scirrhous gastric cancer cells.
Inhibitory effect of a TGFbeta receptor type-I inhibitor, Ki26894, on invasiveness of scirrhous gastric cancer cells.
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DOI：
10.1038/sj.bjc.6605561
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发表时间：
2010-03-02
影响因子：
8.8
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中科院分区：
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胃癌细胞经常转移，部分原因是其高度侵袭性。转化生长因子-β（TGF-β）受体信号传导与癌细胞的侵袭密切相关。本研究旨在探讨TGF-β受体（TGF-βR）磷酸化抑制剂对胃癌细胞侵袭力的影响。使用四种胃癌细胞系，包括两种硬结型细胞系和两种非硬结型细胞系。TβR I型（TβR-I）激酶抑制剂Ki 26894可抑制Smad 2在TβR-I ATP结合位点的磷酸化。我们研究了TβR和磷酸化Smad 2的表达水平，以及TGF-β在Ki 26894存在或不存在的情况下对胃癌细胞的Smad 2磷酸化、侵袭、迁移、上皮向间质转化（EMT）、Ras同源基因家族成员A（RhoA）、ZO-2、肌球蛋白和E-cadherin表达的影响。TβR-I、TβR-II和磷酸化Smad 2在硬化性胃癌细胞中表达，而在非硬化性胃癌细胞中无表达。Ki 26894可抑制TGF-β1诱导的胃癌细胞Smad 2磷酸化。转化生长因子-β1可上调胃癌硬癌细胞的侵袭、迁移和EMT能力。TGF-β1可显著上调硬癌细胞RhoA活性和肌球蛋白磷酸化水平，降低ZO-2和E-cadherin表达。有趣的是，Ki 26894抑制了硬癌胃癌细胞的这些特征。相反，非硬癌胃癌细胞不受TGF-β1或Ki 26894处理的影响。TβR-I激酶抑制剂降低胃硬癌细胞侵袭力和EMT因此，Ki 26894被认为是一种有前途的治疗性化合物，用于硬化性胃癌的转移。
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. 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. 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. 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.