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Targeting eIF4A-Dependent Translation of KRAS Signaling Molecules
- Source :
- Cancer Res
- Publication Year :
- 2021
- Publisher :
- American Association for Cancer Research (AACR), 2021.
-
Abstract
- Pancreatic adenocarcinoma (PDAC) epitomizes a deadly cancer driven by abnormal KRAS signaling. Here, we show that the eIF4A RNA helicase is required for translation of key KRAS signaling molecules and that pharmacological inhibition of eIF4A has single-agent activity against murine and human PDAC models at safe dose levels. EIF4A was uniquely required for the translation of mRNAs with long and highly structured 5′ untranslated regions, including those with multiple G-quadruplex elements. Computational analyses identified these features in mRNAs encoding KRAS and key downstream molecules. Transcriptome-scale ribosome footprinting accurately identified eIF4A-dependent mRNAs in PDAC, including critical KRAS signaling molecules such as PI3K, RALA, RAC2, MET, MYC, and YAP1. These findings contrast with a recent study that relied on an older method, polysome fractionation, and implicated redox-related genes as eIF4A clients. Together, our findings highlight the power of ribosome footprinting in conjunction with deep RNA sequencing in accurately decoding translational control mechanisms and define the therapeutic mechanism of eIF4A inhibitors in PDAC.Significance:These findings document the coordinate, eIF4A-dependent translation of RAS-related oncogenic signaling molecules and demonstrate therapeutic efficacy of eIF4A blockade in pancreatic adenocarcinoma.
- Subjects :
- 0301 basic medicine
Cancer Research
endocrine system diseases
medicine.disease_cause
Mice
Phosphatidylinositol 3-Kinases
0302 clinical medicine
Cycloheximide
Protein Synthesis Inhibitors
YAP1
Translation (biology)
Proto-Oncogene Proteins c-met
RNA Helicase A
RALA
rac GTP-Binding Proteins
Oncology
030220 oncology & carcinogenesis
KRAS
Oxidation-Reduction
RNA Helicases
Cell signaling
Mice, Nude
Adenocarcinoma
Biology
Article
Proto-Oncogene Proteins c-myc
Proto-Oncogene Proteins p21(ras)
03 medical and health sciences
Cell Line, Tumor
medicine
Animals
Humans
RNA, Messenger
Adaptor Proteins, Signal Transducing
Sequence Analysis, RNA
RNA
YAP-Signaling Proteins
Triterpenes
digestive system diseases
G-Quadruplexes
Pancreatic Neoplasms
Genes, ras
030104 developmental biology
Polyribosomes
Protein Biosynthesis
eIF4A
Eukaryotic Initiation Factor-4A
Mutation
Cancer research
ral GTP-Binding Proteins
5' Untranslated Regions
Transcriptome
Ribosomes
Neoplasm Transplantation
Transcription Factors
Subjects
Details
- ISSN :
- 15387445 and 00085472
- Volume :
- 81
- Database :
- OpenAIRE
- Journal :
- Cancer Research
- Accession number :
- edsair.doi.dedup.....123388f6ad013931344f06084ec02cbf