title: Translation Inhibition by Rocaglates Is Independent of eIF4E Phosphorylation Status.
abstract: Rocaglates are natural products that inhibit protein synthesis in eukaryotes and exhibit antineoplastic activity. In vitro biochemical assays, affinity chromatography experiments coupled with mass spectrometry analysis, and in vivo genetic screens have identified eukaryotic initiation factor (eIF) 4A as a direct molecular target of rocaglates. eIF4A is the RNA helicase subunit of eIF4F, a complex that mediates cap-dependent ribosome recruitment to mRNA templates. The eIF4F complex has been implicated in tumor initiation and maintenance through elevated levels or increased phosphorylation status of its cap-binding subunit, eIF4E, thus furthering the interest toward developing rocaglates as antineoplastic agents. Recent experiments have indicated that rocaglates also interact with prohibitins 1 and 2, proteins implicated in c-Raf-MEK-ERK signaling. Because increased ERK signaling stimulates eIF4E phosphorylation status, rocaglates are also expected to inhibit eIF4E phosphorylation status, a point that has not been thoroughly investigated. It is currently unknown whether the effects on translation observed with rocaglates are solely through eIF4A inhibition or also a feature of blocking eIF4E phosphorylation. Here, we show that rocaglates inhibit translation through an eIF4E phosphorylation-independent mechanism.
authors.affiliation: Department of Biochemistry, McGill University, Montreal, Québec, Canada.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Chu
authors.affiliation: Department of Biochemistry, McGill University, Montreal, Québec, Canada.
authors.forename: Regina
authors.initials: R
authors.lastname: Cencic
authors.affiliation: Department of Chemistry, Center for Molecular Discovery (BU-CMD), Boston University, Boston, Massachusetts.
authors.forename: Wenyu
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Chemistry, Center for Molecular Discovery (BU-CMD), Boston University, Boston, Massachusetts.
authors.forename: John A
authors.initials: JA
authors.lastname: Porco
authors.affiliation: Department of Biochemistry, McGill University, Montreal, Québec, Canada. The Rosalind and Morris Goodman Cancer Research Center, McGill University, Montreal, Québec, Canada. Department of Oncology, McGill University, Montreal, Québec, Canada. jerry.pelletier@mcgill.ca.
authors.forename: Jerry
authors.initials: J
authors.lastname: Pelletier
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001572:Benzofurans / Q000494:pharmacology*; D001688:Biological Products / Q000494:pharmacology*; D002460:Cell Line; D003517:Cyclopentanes / Q000494:pharmacology*; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism*; D006801:Humans; D010766:Phosphorylation / Q000187:drug effects; D014176:Protein Biosynthesis / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D001572:Benzofurans; D001688:Biological Products; D003517:Cyclopentanes; D039561:Eukaryotic Initiation Factor-4E