ABSTRACT
The translational control of oncoprotein expression is implicated in many cancers. Here we report an eIF4A RNA helicase-dependent mechanism of translational control that contributes to oncogenesis and underlies the anticancer effects of silvestrol and related compounds. For example, eIF4A promotes T-cell acute lymphoblastic leukaemia development in vivo and is required for leukaemia maintenance. Accordingly, inhibition of eIF4A with silvestrol has powerful therapeutic effects against murine and human leukaemic cells in vitro and in vivo. We use transcriptome-scale ribosome footprinting to identify the hallmarks of eIF4A-dependent transcripts. These include 5' untranslated region (UTR) sequences such as the 12-nucleotide guanine quartet (CGG)4 motif that can form RNA G-quadruplex structures. Notably, among the most eIF4A-dependent and silvestrol-sensitive transcripts are a number of oncogenes, superenhancer-associated transcription factors, and epigenetic regulators. Hence, the 5' UTRs of select cancer genes harbour a targetable requirement for the eIF4A RNA helicase.
Subject(s)
5' Untranslated Regions/genetics , Eukaryotic Initiation Factor-4A/metabolism , G-Quadruplexes , Oncogene Proteins/biosynthesis , Oncogene Proteins/genetics , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Protein Biosynthesis , Animals , Antineoplastic Agents, Phytogenic/pharmacology , Antineoplastic Agents, Phytogenic/therapeutic use , Base Sequence , Cell Line, Tumor , Epigenesis, Genetic , Female , Humans , Mice , Mice, Inbred C57BL , Nucleotide Motifs , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Protein Biosynthesis/drug effects , Ribosomes/metabolism , Transcription Factors/metabolism , Transcription, Genetic/drug effects , Transcription, Genetic/genetics , Triterpenes/pharmacologyABSTRACT
The rocaglates/rocaglamides are a class of natural products known to display potent anticancer activity. One such derivative, silvestrol, has shown activity comparable to taxol in certain settings. Here, we report the synthesis of various rocaglamide analogues and identification of a hydroxamate derivative (-)-9 having activity similar to silvestrol in vitro and ex vivo for inhibition of protein synthesis. We also show that (-)-9 synergizes with doxorubicin in vivo to reduce Eµ-Myc driven lymphomas.
