The natural anticancer compounds rocaglamides inhibit the Raf-MEK-ERK pathway by targeting prohibitin 1 and 2.
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Polier G, Neumann J, Thuaud F, Ribeiro N, Gelhaus C, Schmidt H, Giaisi M, Kohler R, Muller WW, Proksch P, Leippe M, Janssen O, Desaubry L, Krammer PH, Li-Weber M
The natural anticancer compounds rocaglamides inhibit the Raf-MEK-ERK pathway by targeting prohibitin 1 and 2.
Chem Biol. 2012 Sep 21;19(9):1093-104. doi: 10.1016/j.chembiol.2012.07.012.
- PubMed ID
- 22999878 [ View in PubMed]
- Abstract
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.
DrugBank Data that Cites this Article
- Drugs
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Didesmethylrocaglamide Prohibitin Protein Humans YesInhibitorDetails Didesmethylrocaglamide Prohibitin-2 Protein Humans YesInhibitorDetails Rocaglamide Prohibitin Protein Humans YesInhibitorDetails Rocaglamide Prohibitin-2 Protein Humans YesInhibitorDetails