Baicalein induces cancer cell death and proliferation retardation by the inhibition of CDC2 kinase and survivin associated with opposite role of p38 mitogen-activated protein kinase and AKT
Baicalein induces cancer cell death and proliferation retardation by the inhibition of CDC2 kinase and survivin associated with opposite role of p38 mitogen-activated protein kinase and AKT
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DOI：
10.1158/1535-7163.mct-07-0281
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发表时间：
2007-11-01
影响因子：
5.7
通讯作者：
Liu, Huei-Fang
中科院分区：
文献类型：
--
作者：
Chao, Jui-I;Su, Wen-Chi;Liu, Huei-Fang
生物活性黄酮类黄芩素已被证明在体外对人类癌细胞具有生长抑制活性，尽管其作用机制尚不清楚。与其他黄酮类化合物(黄芩苷、儿茶素、染料木素、槲皮素和芦丁)相比，黄芩素(40-80 MU/L作用24小时)更能有效地诱导膀胱癌细胞的细胞毒作用。黄芩素可诱导细胞增殖抑制和细胞凋亡。细胞周期蛋白B1和磷酸化CDC2(Thr(161))水平降低，而G(2)-M期升高。应用CDC2激酶或CDC25磷酸酶抑制剂可增强黄芩素诱导的细胞毒作用。多种人膀胱癌细胞株表达Survivin蛋白，位于有丝分裂相并调节有丝分裂进程。黄芩素显著降低Survivin蛋白的表达。转染Survivin小干扰RNA可降低Survivin蛋白水平，增加黄芩素诱导的细胞死亡。Survivin过表达可促进细胞增殖，拮抗黄芩素的细胞毒作用。有趣的是，黄芩素诱导p38丝裂原活化蛋白激酶(MAPK)和AKT的磷酸化。特异性p38 MAPK抑制剂SB203580可减弱细胞增殖抑制，恢复细胞内磷酸化CDC2(Thr(161))和Survivin的蛋白表达水平；相反，阻断AKT激活可增强细胞毒作用，降低磷酸化CDC2(Thr(161))和Survivin蛋白的表达。综上所述，这些发现表明p38MAPK和AKT对CDC2激酶和Survivin具有相反的调节作用，并且黄芩素抑制CDC2-Survivin通路参与了癌细胞的凋亡和增殖抑制。[摩尔癌症治疗2007；6(11)：3039-48]。
The bioactive flavonoid baicalein has been shown to have in vitro growth-inhibitory activity in human cancer cells, although the mechanism of action is poorly understood. Baicalein (40-80 mu mol/L for 24 h) more effectively induced cytotoxicity compared with other flavonoids (baicalin, catechin, genistein, quercetin, and rutin) in bladder cancer cells. Baicalein induced cell proliferation inhibition and apoptosis. The levels of cyclin B1 and phospho-CDC2 (Thr(161)) were reduced, whereas the G(2)-M phases were elevated by baicalein. Treatment of CDC2 kinase or CDC25 phosphatase inhibitors augments the baicalein-induced cytotoxicity. A variety of human bladder cancer cell lines expressed survivin proteins, which were located on the mitotic phases and regulated mitotic progression. Baicalein markedly reduced survivin protein expression. Transfection of a survivin small interfering RNA diminished the level of survivin proteins and increased the baicalein-mediated cell death. Overexpression of survivin enhanced cell proliferation and resisted the baicalein-induced cytotoxicity. Interestingly, baicalein induced the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and AKT. SB203580, a specific p38 MAPK inhibitor, attenuated proliferation inhibition and restored the protein levels of phospho-CDC2 (Thr(161)) and survivin in the baicalein-exposed cells; conversely, blockade of AKT activation enhanced cytotoxicity and the reduction of phospho-CDC2 (Thr(161)) and survivin proteins. As a whole, these findings provide that the opposite role of p38 MAPK and AKT regulates CDC2 kinase and survivin and the inhibition of CDC2-survivin pathway by baicalein contributes to apoptosis and proliferation retardation in cancer cells. [Mol Cancer Ther 2007;6(11):3039-48].