mTORC1 is a target of nordihydroguaiaretic acid to prevent breast tumor growth in vitro and in vivo
mTORC1 is a target of nordihydroguaiaretic acid to prevent breast tumor growth in vitro and in vivo
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mTORC1 是去甲二氢愈创木酸的靶标，可在体外和体内预防乳腺肿瘤生长
DOI：
10.1007/s10549-012-2270-7
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发表时间：
2012-09
影响因子：
3.8
通讯作者：
Song Q
中科院分区：
文献类型：
--
作者：
Bai X;Xu S;LIn J;Yao G;Han Z;Liang B;Zou Z;Chen Z;Song Q
去甲二氢愈创木酸(NDGA)是从竹节油中分离得到的一种天然酚类化合物，具有体内外抗肿瘤活性。它的类似物正在临床开发中，用于难治性实体肿瘤。但NDGA的抗癌作用机制尚不完全清楚。在这项研究中，我们在培养的乳腺癌细胞和异种移植模型中都确定了哺乳动物雷帕霉素复合体1的靶点(MTORC1)作为NDGA的靶点。NDGA能有效抑制乳腺癌细胞mTORC1的基础水平，但不能抑制mTORC2的活性。抑制细胞周期蛋白D1、缺氧诱导因子α和血管内皮生长因子的表达，抑制乳腺癌细胞的增殖。虽然NDGA刺激AMP激活的蛋白激酶(AMPK)/结节性硬化症复合体2(TSC2)信号转导负调控mTORC1，但AMPK和TSC2的缺失并不能减弱NDGA对mTORC1的抑制作用。随后的研究表明，NDGA也可能直接靶向mTORC1复合体，因为NDGA抑制氨基酸和胰岛素刺激的mTORC1，并像雷帕霉素一样破坏mTOR-Raptor相互作用。最重要的是，NDGA抑制了乳腺肿瘤的生长，并在异种移植模型中靶向mTORC1及其下游信号。总之，我们的数据为NDGA的活性提供了一个新的机制，这可能有助于解释其抗癌活性。破坏mTOR-Raptor复合体和激活AMPK/TSC信号通路可能是NDGA对mTORC1的抑制作用之一。我们的数据也增加了NDGA作为mTORC1抑制剂对乳腺癌有广泛作用的可能性。
Nordihydroguaiaretic acid (NDGA) is a natural phenolic compound isolated from the creosote bushLarrea divaricata,which has anti-tumor activities both in vitro and in vivo. Its analogs are in clinical development for use in refractory solid tumors. But the mechanisms underlying the anti-cancer effect of NDGA are not fully understood. In this study, we identified mammalian target of rapamycin complex 1 (mTORC1) as a target of NDGA both in cultured breast cancer cells and in xenograft models. NDGA effectively inhibited basal level of mTORC1 but not mTORC2 activity in breast cancer cell lines. NDGA also suppressed mTORC1 downstream signaling such as expression of cyclin D1, hypoxia-inducible factor-α and VEGF, and prevented proliferation in breast cancer cells. Although NDGA stimulated AMP-activated protein kinase (AMPK)/tuberous sclerosis complex 2 (TSC2) signaling, which negatively regulates mTORC1, AMPK and TSC2 deletion could not diminish the inhibition of mTORC1 by NDGA. Subsequent studies revealed that NDGA may also direct target mTORC1 complex because NDGA suppressed amino acids- and insulin-stimulated mTORC1 and acted like rapamycin to disrupt mTOR–Raptor interaction. Most importantly, NDGA repressed breast tumor growth and targeted mTORC1 and its downstream signaling in xenograft models. Together our data provide a novel mechanism for NDGA activity which could help explain its anti-cancer activity. Disruption of mTOR–Raptor complex and activation of AMPK/TSC signaling may contribute to inhibitory effects of NDGA against mTORC1. Our data also raise the possibility that NDGA, as an mTORC1 inhibitor, may have a broad spectrum of action on breast cancers.
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影响因子：
11.2
作者：
D. Rose;J. Connolly
通讯作者：
D. Rose;J. Connolly
影响因子：
4
作者：
Zavodovskaya, Marianna;Campbel, Michael J.;Goldfine, Ira D.
通讯作者：
Goldfine, Ira D.
DOI：
10.1016/j.bbrc.2010.09.016
发表时间：
2010-10-08
影响因子：
3.1
作者：
Lee, Myoung-Su;Kim, Daeyoung;Hwang, Jae-Kwan
通讯作者：
Hwang, Jae-Kwan
影响因子：
4
作者：
Huang, S;Houghton, PJ
通讯作者：
Houghton, PJ
影响因子：
7.5
作者：
Efeyan A;Sabatini DM
通讯作者：
Sabatini DM