Polier Gernot, Neumann Jennifer, Thuaud Frédéric, Ribeiro Nigel, Gelhaus Christoph, Schmidt Hendrik, Giaisi Marco, Köhler Rebecca, Müller Wolfgang W, Proksch Peter, Leippe Matthias, Janssen Ottmar, Désaubry Laurent, Krammer Peter H, Li-Weber Min
Tumorimmunology Program (D030), German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany.
Chem Biol. 2012 Sep 21;19(9):1093-104. doi: 10.1016/j.chembiol.2012.07.012.
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-eIF4 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.
洛卡酰胺是强效的天然抗癌产物，能在纳摩尔浓度下抑制多种癌细胞的增殖。我们最近发现，这些化合物通过阻断MEK-ERK-eIF4途径来阻止肿瘤生长并使耐药癌细胞对凋亡敏感。然而，它们的直接分子靶点仍然未知。在本研究中，我们使用亲和色谱法发现，抗增殖蛋白（PHB）1和2是洛卡酰胺的直接靶点。洛卡酰胺与PHB的结合会阻止PHB与C-Raf之间的相互作用，从而抑制C-Raf的激活以及随后的C-Raf-MEK-ERK信号传导。此外，敲低PHB可模拟洛卡酰胺对C-Raf-MEK-ERK途径和细胞周期进程的影响。因此，我们的发现表明，洛卡酰胺是一种新型抗癌剂，它们可能作为研究PHB介导的细胞过程的小分子工具。
