title: The natural anticancer compounds rocaglamides inhibit the Raf-MEK-ERK pathway by targeting prohibitin 1 and 2.
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.
authors.affiliation: Tumorimmunology Program (D030), German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany.
authors.forename: Gernot
authors.initials: G
authors.lastname: Polier
authors.forename: Jennifer
authors.initials: J
authors.lastname: Neumann
authors.forename: Frédéric
authors.initials: F
authors.lastname: Thuaud
authors.forename: Nigel
authors.initials: N
authors.lastname: Ribeiro
authors.forename: Christoph
authors.initials: C
authors.lastname: Gelhaus
authors.forename: Hendrik
authors.initials: H
authors.lastname: Schmidt
authors.forename: Marco
authors.initials: M
authors.lastname: Giaisi
authors.forename: Rebecca
authors.initials: R
authors.lastname: Köhler
authors.forename: Wolfgang W
authors.initials: WW
authors.lastname: Müller
authors.forename: Peter
authors.initials: P
authors.lastname: Proksch
authors.forename: Matthias
authors.initials: M
authors.lastname: Leippe
authors.forename: Ottmar
authors.initials: O
authors.lastname: Janssen
authors.forename: Laurent
authors.initials: L
authors.lastname: Désaubry
authors.forename: Peter H
authors.initials: PH
authors.lastname: Krammer
authors.forename: Min
authors.initials: M
authors.lastname: Li-Weber
mesh_terms: D031602:Aglaia / Q000737:chemistry; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D001572:Benzofurans / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004354:Drug Screening Assays, Antitumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D000091402:Prohibitins; D019908:Proto-Oncogene Proteins c-raf / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D001572:Benzofurans; C000717328:PHB protein, human; D000091402:Prohibitins; D012097:Repressor Proteins; C107772:rocaglamide; D019908:Proto-Oncogene Proteins c-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases