EIF4A supports an oncogenic translation program in pancreatic ductal adenocarcinoma.
Date
2019-11-13
Authors
Chan, Karina
Robert, Francis
Oertlin, Christian
Kapeller-Libermann, Dana
Avizonis, Daina
Gutierrez, Johana
Handly-Santana, Abram
Doubrovin, Mikhail
Park, Julia
Schoepfer, Christina
Version
Published version
OA Version
Citation
Karina Chan, Francis Robert, Christian Oertlin, Dana Kapeller-Libermann, Daina Avizonis, Johana Gutierrez, Abram Handly-Santana, Mikhail Doubrovin, Julia Park, Christina Schoepfer, Brandon Da Silva, Melissa Yao, Faith Gorton, Junwei Shi, Craig J. Thomas, Lauren E. Brown, John A. Porco, Michael Pollak, Ola Larsson, Jerry Pelletier, Iok In Christine Chio. 2019. "eIF4A supports an oncogenic translation program in pancreatic ductal adenocarcinoma.." Nat Commun, Volume 10, Issue 1. https://doi.org/10.1038/s41467-019-13086-5
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.
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