Inhibition of the proteasome activity, a novel mechanism associated with the tumor cell apoptosis-inducing ability of genistein
Inhibition of the proteasome activity, a novel mechanism associated with the tumor cell apoptosis-inducing ability of genistein
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DOI：
10.1016/s0006-2952(03)00414-3
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发表时间：
2003-09-15
影响因子：
5.8
通讯作者：
Dou, QP
中科院分区：
文献类型：
--
作者：
Kazi, A;Daniel, KG;Dou, QP
流行病学研究表明，大豆消费量的增加与癌症发生率的降低有关。染料木黄酮一种大豆多糖，已经报道抑制人肿瘤细胞的生长，尽管所涉及的分子机制还没有明确定义。在这里，我们报告，染料木素抑制蛋白酶体胰凝乳蛋白酶样活性在体外和体内。计算对接研究表明，染料木素与蛋白酶体β 5亚基的相互作用是负责胰凝乳蛋白酶样活性的抑制。在前列腺癌LNCaP和乳腺癌MCF-7细胞中，染料木素对蛋白酶体的抑制与泛素化蛋白和三种已知蛋白酶体靶蛋白（细胞周期蛋白依赖性激酶抑制剂p27（Kip 1）、核因子-κ B抑制剂（IkappaB-alpha）和促凋亡蛋白Bax）的积累有关。染料木素介导的蛋白酶体抑制伴随着诱导这些实体瘤细胞的凋亡。最后，金雀异黄素诱导蛋白酶体抑制和细胞凋亡选择性猿猴病毒40转化的人成纤维细胞，但不是在他们的父母正常的对应。我们的研究结果表明，蛋白酶体是一个潜在的目标，染料木素在人类肿瘤细胞和抑制蛋白酶体活性染料木素可能有助于其预防癌症的性质。(C)2003年爱思唯尔公司All rights reserved.
Epidemiological studies have suggested that increased soy consumption is associated with reduced cancer occurrence. Genistein. a soy isoflavone, has been reported to inhibit the growth of human tumor cells although the involved molecular mechanisms are not clearly defined. Here we report that genistein inhibits the proteasomal chymotrypsin-like activity in vitro and in vivo. Computational docking studies suggest that the interaction of genistein with the proteasomal beta5 subunit is responsible for inhibition of the chymotrypsin-like activity. Inhibition of the proteasome by genistein in prostate cancer LNCaP and breast cancer MCF-7 cells is associated with accumulation of ubiquitinated proteins and three known proteasome target proteins, the cyclin-dependent kinase inhibitor p27(Kip1), inhibitor of nuclear factor-kappaB (IkappaB-alpha), and the pro-apoptotic protein Bax. Genistein-mediated proteasome inhibition was accompanied by induction of apoptosis in these solid tumor cells. Finally, genistein induced proteasome inhibition and apoptosis selectively in simian virus 40-transformed human fibroblasts, but not in their parental normal counterpart. Our results suggest that the proteasome is a potential target of genistein in human tumor cells and that inhibition of the proteasome activity by genistein might contribute to its cancer-preventive properties. (C) 2003 Elsevier Inc. All rights reserved.