Equol, a metabolite of the soybean isoflavone daidzein, inhibits neoplastic cell transformation by targeting the MEK/ERK/p90RSK/activator protein-1 pathway
Equol, a metabolite of the soybean isoflavone daidzein, inhibits neoplastic cell transformation by targeting the MEK/ERK/p90RSK/activator protein-1 pathway
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DOI：
10.1074/jbc.m701459200
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发表时间：
2007-11-09
影响因子：
4.8
通讯作者：
Dong, Zigang
中科院分区：
文献类型：
--
作者：
Kang, Nam Joo;Lee, Ki Won;Dong, Zigang
大豆苷元和染料木素是大豆中发现的异黄酮类化合物。已知金雀异黄素具有抗癌活性和抑制酪氨酸激酶活性。然而，大豆苷元及其代谢物Equol的化学预防作用的潜在分子机制尚不清楚。在此，我们报道了QUOL通过靶向MEK/ERK/p90RSK/Actiator Protein-1信号通路抑制12-O-十四酰佛波醇-13-乙酸酯(TPA)诱导的JB6P+小鼠表皮细胞的肿瘤转化。在非细胞毒性浓度下，QUOL以剂量依赖的方式抑制TPA诱导的肿瘤细胞转化，而大豆苷元无此作用。Equol呈剂量依赖性地减弱TPA诱导的激活蛋白-1和c-fos的激活，而大豆苷元在相同浓度下没有任何影响。QUOL可抑制TPA诱导的ERK1/2、p90RSK和ELK的磷酸化，而MEK和c-jun氨基末端的磷酸化不受大豆苷元的抑制。体外激酶分析显示，在JB6P+细胞裂解物中，乙醇能显著抑制MEK1的活性，但不能抑制Raf1的活性；体外的激酶分析也表明，它能抑制TPA诱导的JB6P+细胞裂解物中MEK1的活性。EQOL剂量依赖地抑制表皮生长因子或H-RAS诱导的JB6 P+细胞的恶性转化。体外和体外下拉实验均表明，乙醇直接与谷胱甘肽S转移酶-MEK1结合，抑制MEK1的活性，而不与三磷酸腺苷竞争。这些结果提示，马兜铃醇的抗肿瘤作用主要是通过靶向MEK信号通路来抑制细胞转化。这些发现首次揭示了雌马酚抗癌作用的分子基础，并可能部分解释了已报道的大豆的化学预防作用。
Daidzein and genistein are isoflavones found in soybean. Genistein is known to exhibit anticarcinogenic activities and inhibit tyrosine kinase activity. However, the underlying molecular mechanisms of the chemopreventive activities of daidzein and its metabolite, equol, are not understood. Here we report that equol inhibits 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced neoplastic transformation of JB6 P+ mouse epidermal cells by targeting the MEK/ERK/p90RSK/activator protein-1 signaling pathway. TPA-induced neoplastic cell transformation was inhibited by equol, but not daidzein, at noncytotoxic concentrations in a dose-dependent manner. Equol dose-dependently attenuated TPA-induced activation of activator protein-1 and c-fos, whereas daidzein did not exert any effect when tested at the same concentrations. The TPA-induced phosphorylation of ERK1/2, p90RSK, and Elk, but not MEK or c-Jun N-terminal kinase, was inhibited by equol but not by daidzein. In vitro kinase assays revealed that equol greatly inhibited MEK1, but not Raf1, kinase activity, and an ex vivo kinase assay also demonstrated that equol suppressed TPA-induced MEK1 kinase activity in JB6 P+ cell lysates. Equol dose-dependently inhibited neoplastic transformation of JB6 P+ cells induced by epidermal growth factor or H-Ras. Both in vitro and ex vivo pull-down assays revealed that equol directly bound with glutathione S-transferase-MEK1 to inhibit MEK1 activity without competing with ATP. These results suggested that the antitumor-promoting effect of equol is due to the inhibition of cell transformation mainly by targeting a MEK signaling pathway. These findings are the first to reveal a molecular basis for the anticancer action of equol and may partially account for the reported chemopreventive effects of soybean.