Wedelolactone Acts as Proteasome Inhibitor in Breast Cancer Cells.
Wedelolactone Acts as Proteasome Inhibitor in Breast Cancer Cells.
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DOI：
10.3390/ijms18040729
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发表时间：
2017-03-29
影响因子：
5.6
通讯作者：
Beneš P
中科院分区：
文献类型：
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作者：
Nehybová T;Šmarda J;Daniel L;Stiborek M;Kanický V;Spasojevič I;Preisler J;Damborský J;Beneš P
Wedelolactone是一种多靶点的天然植物香豆素，对癌细胞具有细胞毒性。虽然已经认识到了几个分子靶标，但其细胞毒性的分子机制尚未阐明。在这项研究中，我们表明，wedelolactone作为一种抑制剂糜蛋白酶样，胰蛋白酶样，半胱天冬酶样活性的蛋白酶体在乳腺癌细胞。通过（i）荧光蛋白酶体底物的切割减少;（ii）肿瘤细胞中多聚泛素化蛋白和快速周转蛋白的积累;和（iii）将wedelolactone分子对接到蛋白酶体催化亚基的活性位点，证明了wedelolactone的蛋白酶体抑制作用。抑制蛋白酶体的wedelolactone是独立的能力，诱导活性氧产生的氧化还原循环与铜离子，表明wedelolactone作为铜非依赖性蛋白酶体抑制剂。我们的结论是，wedelolactone对乳腺癌细胞的细胞毒作用部分介导的靶向蛋白酶体蛋白降解途径。理解wedelolactone抑制模式的结构基础可能有助于为设计有效抑制癌细胞的新型化合物开辟新的途径。
Wedelolactone is a multi-target natural plant coumestan exhibiting cytotoxicity towards cancer cells. Although several molecular targets of wedelolactone have been recognized, the molecular mechanism of its cytotoxicity has not yet been elucidated. In this study, we show that wedelolactone acts as an inhibitor of chymotrypsin-like, trypsin-like, and caspase-like activities of proteasome in breast cancer cells. The proteasome inhibitory effect of wedelolactone was documented by (i) reduced cleavage of fluorogenic proteasome substrates; (ii) accumulation of polyubiquitinated proteins and proteins with rapid turnover in tumor cells; and (iii) molecular docking of wedelolactone into the active sites of proteasome catalytic subunits. Inhibition of proteasome by wedelolactone was independent on its ability to induce reactive oxygen species production by redox cycling with copper ions, suggesting that wedelolactone acts as copper-independent proteasome inhibitor. We conclude that the cytotoxicity of wedelolactone to breast cancer cells is partially mediated by targeting proteasomal protein degradation pathway. Understanding the structural basis for inhibitory mode of wedelolactone might help to open up new avenues for design of novel compounds efficiently inhibiting cancer cells.