Ki26894, a novel transforming growth factor-β type I receptor kinase inhibitor, inhibits in vitro invasion and in vivo bone metastasis of a human breast cancer cell line
Ki26894, a novel transforming growth factor-β type I receptor kinase inhibitor, inhibits in vitro invasion and in vivo bone metastasis of a human breast cancer cell line
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DOI：
10.1111/j.1349-7006.2006.00357.x
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发表时间：
2007-01-01
期刊：
影响因子：
5.7
通讯作者：
Imamura, Takeshi
中科院分区：
文献类型：
--
作者：
Ehata, Shogo;Hanyu, Aki;Imamura, Takeshi
转化生长因子（TGF）-β信号转导已被证明促进晚期癌症中的肿瘤生长和转移。因此，使用TGF-β信号传导抑制剂可能是治疗此类癌症患者的新策略。在这项研究中，我们研究了一种新的TGF-β I型受体（T β R-I）激酶抑制剂Ki 26894对人乳腺癌MDA-MB-231细胞（称为MDA-MB-231-5a-D（MDA-231-D））的高骨转移变体骨转移的影响。Ki 26894阻断了MDA-231-D细胞中的TGF-β信号传导，如通过抑制Smad 2的磷酸化和抑制TGF-β反应性报告活性所检测到的。此外，Ki 26894还能抑制TGF-β诱导的MDA-231-D细胞的运动和侵袭能力。Ki 26894还抑制TGF-β刺激的MDA-231-D细胞的纤溶酶原激活物抑制剂-1（派-1）、甲状旁腺相关蛋白（PTHrP）和白细胞介素-11（IL-11）mRNA的转录。X射线照相术显示，在将MDA-231-D细胞接种到BALB/c nu/nu雌性小鼠的左心室中之前1天开始的系统性Ki 26894治疗导致乳腺癌细胞的骨转移减少。此外，与溶剂处理的小鼠相比，Ki 26894延长了接种MDA-231-D细胞的小鼠的存活时间。这些发现表明，T β R-I激酶抑制剂如Ki 26894可能有助于阻断晚期癌症的进展。
Transforming growth factor (TGF)-beta signaling has been shown to promote tumor growth and metastasis in advanced cancer. Use of inhibitors of TGF-beta signaling may thus be a novel strategy for treatment of patients with such cancers. In this study, we investigated the effects of a novel TGF-beta type I receptor (T beta R-I) kinase inhibitor, Ki26894, on bone metastasis of a highly bone-metastatic variant of human breast cancer MDA-MB-231 cells, termed MDA-MB-231-5a-D (MDA-231-D). Ki26894 blocked TGF-beta signaling in MDA-231-D cells, as detected by suppression of phosphorylation of Smad2 and inhibition of TGF-beta-responsive reporter activity. Moreover, Ki26894 decreased the motility and the invasion of MDA-231-D cells induced by TGF-beta in vitro. Ki26894 also suppressed transcription of plasminogen activator inhibitor-1 (PAI-1), parathyroid hormone-related protein (PTHrP), and interleukin-11 (IL-11) mRNA of MDA-231-D cells, which were stimulated by TGF-beta. X-ray radiography revealed that systemic Ki26894 treatment initiated 1 day before the inoculation of MDA-231-D cells into the left ventricle of BALB/c nu/nu female mice resulted in decreased bone metastasis of breast cancer cells. Moreover, Ki26894 prolonged the survival of mice inoculated with MDA-231-D cells compared to vehicle-treated mice. These findings suggest that T beta R-I kinase inhibitors such as Ki26894 may be useful for blocking the progression of advanced cancers.