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eIF4A supports an oncogenic translation program in pancreatic ductal adenocarcinoma

Author

Listed:
  • Karina Chan

    (Columbia University Medical Center)

  • Francis Robert

    (McGill University)

  • Christian Oertlin

    (Karolinska Institute)

  • Dana Kapeller-Libermann

    (Columbia University Medical Center)

  • Daina Avizonis

    (McGill University)

  • Johana Gutierrez

    (Columbia University Medical Center)

  • Abram Handly-Santana

    (Columbia University Medical Center
    Cold Spring Harbor Laboratory)

  • Mikhail Doubrovin

    (Columbia University Medical Center)

  • Julia Park

    (Cold Spring Harbor Laboratory
    University of Pennsylvania)

  • Christina Schoepfer

    (Cold Spring Harbor Laboratory)

  • Brandon Silva

    (Cold Spring Harbor Laboratory
    SUNY Downstate College of Medicine, SUNY Downstate Medical Center)

  • Melissa Yao

    (Cold Spring Harbor Laboratory)

  • Faith Gorton

    (Cold Spring Harbor Laboratory)

  • Junwei Shi

    (University of Pennsylvania)

  • Craig J. Thomas

    (National Cancer Institute)

  • Lauren E. Brown

    (Boston University)

  • John A. Porco

    (Boston University)

  • Michael Pollak

    (McGill University)

  • Ola Larsson

    (Karolinska Institute)

  • Jerry Pelletier

    (McGill University)

  • Iok In Christine Chio

    (Columbia University Medical Center)

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.

Suggested Citation

  • Karina Chan & Francis Robert & Christian Oertlin & Dana Kapeller-Libermann & Daina Avizonis & Johana Gutierrez & Abram Handly-Santana & Mikhail Doubrovin & Julia Park & Christina Schoepfer & Brandon S, 2019. "eIF4A supports an oncogenic translation program in pancreatic ductal adenocarcinoma," Nature Communications, Nature, vol. 10(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-13086-5
    DOI: 10.1038/s41467-019-13086-5
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    Cited by:

    1. Weiqiang Lu & Jiayan Cui & Wanyan Wang & Qian Hu & Yun Xue & Xi Liu & Ting Gong & Yiping Lu & Hui Ma & Xinyu Yang & Bo Feng & Qi Wang & Naixia Zhang & Yechun Xu & Mingyao Liu & Ruth Nussinov & Feixion, 2024. "PPIA dictates NRF2 stability to promote lung cancer progression," Nature Communications, Nature, vol. 15(1), pages 1-20, December.

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