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Updated: Jan 3, 2026
Monitoring eIF4F Assembly by Measuring eIF4E-eIF4G Interaction in Live Cells
Published on: May 1, 2020
eIF4A supports an oncogenic translation program in pancreatic ductal adenocarcinoma
Karina Chan1, Francis Robert2, Christian Oertlin3
1Institute for Cancer Genetics, Department of Genetics and Development, Columbia University Medical Center, New York, NY, 10032, USA.
Abstract:
Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy with limited treatment options. Although metabolic reprogramming is a hallmark of many cancers, including PDA, previous attempts to target metabolic changes therapeutically have been stymied by drug toxicity and tumour cell plasticity. Here, we show that PDA cells engage an eIF4F-dependent translation program that supports redox and central carbon metabolism. Inhibition of the eIF4F subunit, eIF4A, using the synthetic rocaglate CR-1-31-B (CR-31) reduced the viability of PDA organoids relative to their normal counterparts. In vivo, CR-31 suppresses tumour growth and extends survival of genetically-engineered murine models of PDA. Surprisingly, inhibition of eIF4A also induces glutamine reductive carboxylation. As a consequence, combined targeting of eIF4A and glutaminase activity more effectively inhibits PDA cell growth both in vitro and in vivo. Overall, our work demonstrates the importance of eIF4A in translational control of pancreatic tumour metabolism and as a therapeutic target against PDA.
Insights
Targeting eIF4A, a key protein in pancreatic cancer cell metabolism, with CR-31 shows promise. Combining this with glutaminase inhibition offers a potent strategy against pancreatic ductal adenocarcinoma (PDA).
Area of Science:
- Oncology
- Molecular Biology
- Cancer Metabolism
Background:
- Pancreatic ductal adenocarcinoma (PDA) is a deadly cancer with few effective treatments.
- Cancer cells, including PDA, reprogram their metabolism, but targeting this has faced challenges due to toxicity and tumor adaptability.
- PDA cells utilize a specific translation program involving eIF4F to support their metabolic needs.
Purpose of the Study:
- To investigate the role of the eIF4F translation program in pancreatic cancer metabolism.
- To evaluate the therapeutic potential of inhibiting eIF4A, a subunit of eIF4F, in PDA.
- To explore combination therapies targeting eIF4A and glutaminase activity.
Main Methods:
- Utilized the synthetic rocaglate CR-1-31-B (CR-31) to inhibit eIF4A activity.
- Assessed the impact of CR-31 on PDA organoid viability and in vivo tumor growth in genetically-engineered mouse models.
- Investigated the metabolic consequences of eIF4A inhibition, including glutamine reductive carboxylation.
- Evaluated the efficacy of combined CR-31 and glutaminase inhibition in PDA models.
Main Results:
- CR-31 significantly reduced PDA organoid viability compared to normal cells.
- In vivo, CR-31 suppressed tumor growth and extended survival in PDA mouse models.
- eIF4A inhibition induced glutamine reductive carboxylation in PDA cells.
- Combined targeting of eIF4A and glutaminase activity demonstrated enhanced inhibition of PDA cell growth in vitro and in vivo.
Conclusions:
- eIF4A plays a critical role in controlling pancreatic tumor cell metabolism through translational regulation.
- Inhibiting eIF4A with CR-31 represents a promising therapeutic strategy for PDA.
- Combination therapy targeting both eIF4A and glutaminase offers a more effective approach to combat PDA.
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