Nordihydroguaiaretic acid inhibits transforming growth factor beta type 1 receptor activity and downstream signaling.
Nordihydroguaiaretic acid inhibits transforming growth factor beta type 1 receptor activity and downstream signaling.
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DOI：
10.1016/j.ejphar.2009.06.012
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发表时间：
2009-08-15
影响因子：
5
通讯作者：
Youngren JF
中科院分区：
文献类型：
--
作者：
Li F;Pham JD;Anderson MO;Youngren JF
去甲二氢愈创木酸（NDGA）是从木馏油灌木Larreatridentate中分离得到的一种酚类木脂素，它在体外和体内都具有抗癌活性。已经确定了几种可能有助于这些作用的机制，因为NDGA直接抑制作为既定抗癌靶点的代谢酶和受体酪氨酸激酶。在本研究中，我们发现NDGA抑制转化生长因子β（TGF-β）I型受体，一种丝氨酸苏氨酸激酶受体。在培养的细胞中，NDGA处理抑制TGF-β处理和TGF-β I型受体的组成型活性突变体（T202 D）诱导的Smad 2磷酸化。NDGA还抑制由TGF-β处理和组成型活性突变体受体介导的下游转录激活。在体外，NDGA抑制TGF-β I型受体介导的Smad 2磷酸化在粗细胞裂解物和纯化的制剂。重要的是，筛选选择的类似物表明，NDGA结构的修饰导致对受体的效力改变。这些结果表明，NDGA的结构可以被修饰以实现增加的效力。总之，我们的数据提供了NDGA活性的新机制，这可以帮助解释其抗癌活性，并表明NDGA可以作为开发对TGF-β I型受体具有选择性的丝氨酸/苏氨酸激酶抑制剂的结构基序。
It has been well documented that nordihydroguaiaretic acid (NDGA), a phenolic lignan isolated from the creosote bush, Larrea tridentate, has anti-cancer activity in vitro and in vivo. Several mechanisms have been identified that could contribute to these actions, as NDGA directly inhibits metabolic enzymes and receptor tyrosine kinases that are established anti-cancer targets. In the present study, we show that NDGA inhibits the transforming growth factor β (TGF-β) type I receptor, a serine threonine kinase receptor. In cultured cells, NDGA treatment repressed Smad2 phosphorylation induced by TGF-β treatment and by a constitutively active mutant of TGF-β type I receptor (T202D). NDGA also inhibited downstream transcriptional activation mediated by both TGF-β treatment and the constitutively active mutant receptor. In vitro, NDGA inhibited TGF-β type I receptor mediated Smad2 phosphorylation in crude cell lysates and in a purified preparation. Importantly, screening select analogs demonstrated that modification of NDGA’s structure resulted in altered potency against the receptor. These results indicated that the structure of NDGA can be modified to achieve increased potency. Together our data provide a novel mechanism for NDGA activity which could help explain its anti-cancer activity, and suggest that NDGA could serve as a structural motif for developing serine/threonine kinase inhibitors with selectivity for TGF-β type I receptor.
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DOI：
10.1016/j.plefa.2006.01.009
发表时间：
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影响因子：
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