A new IκB kinase β inhibitor prevents human breast cancer progression through negative regulation of cell cycle transition
A new IκB kinase β inhibitor prevents human breast cancer progression through negative regulation of cell cycle transition
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DOI：
10.1158/0008-5472.can-05-0741
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发表时间：
2006-01-01
期刊：
影响因子：
11.2
通讯作者：
Matsuda, H
中科院分区：
文献类型：
--
作者：
Tanaka, A;Muto, S;Matsuda, H
组成性核因子-κ B（NF-κ B）活性在淋巴瘤、白血病和一些上皮癌的发生和发展中起着至关重要的作用。鉴于NF-κ B在致癌作用中的作用，一种干扰其活性的新方法可能对传统治疗反应较差的癌症具有治疗潜力。在这里，我们已经表明，一种新的I κ B激酶β抑制剂，IMD-0354，抑制人乳腺癌细胞，MDA-MB-231，HMCI-8和MCF-7的生长，通过阻止细胞周期和诱导凋亡。在电泳迁移率变动分析和报告基因分析中，IMD-0354以剂量依赖性方式消除MDA-MB-231细胞中的NF-κ B活性。在与IMD-0354孵育的细胞中，细胞周期停滞在G 0-G1期，凋亡细胞增加。在用IMD-0354处理的细胞中，一些细胞周期调节分子和抗凋亡分子的表达被抑制。另一方面，通过添加IMD-0354上调细胞周期蛋白依赖性激酶抑制因子p27 KipI。每日给予IMD-0354抑制了移植了MDA-MB-231细胞的免疫缺陷小鼠的肿瘤扩张。这些结果表明，NF-κ B可能通过上调细胞周期进程促进细胞增殖;因此，抑制NF-κ B活性可能在治疗人乳腺癌中具有治疗能力。
Constitutive nuclear factor-kappa B (NF-kappa B) activity plays a crucial role in the development and progression of lymphoma, leukemia, and some epithelial cancers. Given the contribution of NF-kappa B in carcinogenesis, a novel approach that interferes with its activity might have therapeutic potential against cancers that respond poorly to conventional treatments. Here, we have shown that a new I kappa B kinase beta inhibitor, IMD-0354, suppressed the growth of human breast cancer cells, MDA-MB-231, HMCI-8, and MCF-7, by arresting cell cycle and inducing apoptosis. In an electrophoretic mobility shift assay and a reporter assay, IMD-0354 abolished the NF-kappa B activity in MDA-MB-231 cells in a dose-dependent manner. In the cells incubated with IMD-0354, cell cycle arrested at the Go-G, phase and apoptotic cells were increased. The expression of some cell cycle regulatory molecules and antiapoptotic molecules was suppressed in cells treated with IMD-0354. On the other hand, cyclin-dependent kinase suppressor p27KipI was up-regulated by the addition of IMD-0354. Daily administration of IMD-0354 inhibited tumor expansion in immunodeficient mice into which MDA-MB-231 cells were transplanted. These results indicate that NF-kappa B may contribute to cell proliferation through up-regulation of cell cycle progression; accordingly, inhibition of NF-kappa B activity might have a therapeutic ability in the treatment of human breast cancers.