1. The Natural Anticancer Compounds Rocaglamides Inhibit the Raf-MEK-ERK Pathway by Targeting Prohibitin 1 and 2
- Author
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Gernot Polier, Wolfgang W. Müller, Nigel Ribeiro, Marco Giaisi, Ottmar Janssen, Rebecca Köhler, Frédéric Thuaud, Hendrik Schmidt, Peter H. Krammer, Jennifer Neumann, Laurent Désaubry, Peter Proksch, Min Li-Weber, Matthias Leippe, and Christoph Gelhaus
- Subjects
MAP Kinase Signaling System ,Clinical Biochemistry ,macromolecular substances ,Biology ,Biochemistry ,Jurkat cells ,Jurkat Cells ,Structure-Activity Relationship ,chemistry.chemical_compound ,Rocaglamide ,Prohibitins ,Drug Discovery ,Humans ,Prohibitin ,Extracellular Signal-Regulated MAP Kinases ,Molecular Biology ,Cells, Cultured ,Benzofurans ,Cell Proliferation ,Pharmacology ,Gene knockdown ,Cell growth ,Cell Cycle ,HEK 293 cells ,technology, industry, and agriculture ,General Medicine ,Cell cycle ,MAP Kinase Kinase Kinases ,Antineoplastic Agents, Phytogenic ,Cell biology ,Proto-Oncogene Proteins c-raf ,Repressor Proteins ,HEK293 Cells ,chemistry ,Cancer cell ,Molecular Medicine ,lipids (amino acids, peptides, and proteins) ,Drug Screening Assays, Antitumor ,Aglaia ,HeLa Cells - Abstract
SummaryRocaglamides 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.
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