The Natural Anticancer Compounds Rocaglamides Inhibit the Raf-MEK-ERK Pathway by Targeting Prohibitin 1 and 2
The Natural Anticancer Compounds Rocaglamides Inhibit the Raf-MEK-ERK Pathway by Targeting Prohibitin 1 and 2
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DOI：
10.1016/j.chembiol.2012.07.012
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发表时间：
2012-09-21
影响因子：
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通讯作者：
Li-Weber, Min
中科院分区：
文献类型：
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作者：
Polier, Gemot;Neumann, Jennifer;Li-Weber, Min
罗格列胺是一种有效的天然抗癌产品，可在纳摩尔浓度下抑制各种癌细胞的增殖。我们最近已经证明，这些化合物通过阻断MEK-ERK-elF4通路来阻止肿瘤生长，并使耐药癌细胞对凋亡敏感。然而，他们的直接分子靶点(S)(S)仍然未知。在本研究中，利用亲和层析的方法，我们发现禁止素(PHB)1和2是罗格列胺的直接靶标。罗格列胺与PHB的结合阻止了PHB和CRAF之间的相互作用，从而抑制了CRAF的激活，并随后抑制了CRAF-MEK-ERK信号转导。此外，PHB的敲除模拟了罗格列胺对CRAF-MEK-ERK通路和细胞周期进程的影响。因此，我们的发现表明，岩石酰胺类化合物是一种新型的抗癌药物，它们可能成为研究PHB介导的细胞过程的小分子工具。
Rocaglamides are potent natural anticancer products that inhibit proliferation of various cancer cells at nanomolar concentrations. We have recently shown that these compounds prevent tumor growth and sensitize resistant cancer cells to apoptosis by blocking the MEK-ERK-elF4 pathway. However, their direct molecular target(s) remain(s) unknown. In this study, using an affinity chromatography approach we discovered that prohibitin (PHB) 1 and 2 are the direct targets of rocaglamides. Binding of rocaglamides to PHB prevents interaction between PHB and CRaf and, thereby, inhibits CRaf activation and subsequently CRaf-MEK-ERK signaling. Moreover, knockdown of PHB mimicked the effects of rocaglamides on the CRaf-MEK-ERK pathway and cell cycle progression. Thus, our finding suggests that rocaglamides are a new type of anticancer agent and that they may serve as a small-molecular tool for studying PHB-mediated cellular processes.