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MYC sensitises cells to apoptosis by driving energetic demand

Author

Listed:
  • Joy Edwards-Hicks

    (University of Edinburgh
    Max Planck Institute of Immunobiology and Epigenetics)

  • Huizhong Su

    (University of Edinburgh)

  • Maurizio Mangolini

    (University of Cambridge)

  • Kubra K. Yoneten

    (Queen Mary University of London)

  • Jimi Wills

    (University of Edinburgh)

  • Giovanny Rodriguez-Blanco

    (University of Edinburgh)

  • Christine Young

    (University of Edinburgh)

  • Kevin Cho

    (Washington University School of Medicine)

  • Heather Barker

    (University of Edinburgh)

  • Morwenna Muir

    (University of Edinburgh)

  • Ania Naila Guerrieri

    (University of Edinburgh)

  • Xue-Feng Li

    (MRC University of Edinburgh Centre for Reproductive Health, University of Edinburgh)

  • Rachel White

    (University of Edinburgh)

  • Piotr Manasterski

    (University of Edinburgh)

  • Elena Mandrou

    (University of Edinburgh)

  • Karen Wills

    (University of Edinburgh)

  • Jingyu Chen

    (University of Cambridge)

  • Emily Abraham

    (Queen Mary University of London)

  • Kianoosh Sateri

    (Queen Mary University of London)

  • Bin-Zhi Qian

    (University of Edinburgh
    MRC University of Edinburgh Centre for Reproductive Health, University of Edinburgh)

  • Peter Bankhead

    (University of Edinburgh)

  • Mark Arends

    (University of Edinburgh)

  • Noor Gammoh

    (University of Edinburgh)

  • Alex von Kriegsheim

    (University of Edinburgh)

  • Gary J. Patti

    (Washington University School of Medicine)

  • Andrew H. Sims

    (University of Edinburgh)

  • Juan Carlos Acosta

    (University of Edinburgh
    IBBTEC (CSIC, Universidad de Cantabria). C/ Albert Einstein 22)

  • Valerie Brunton

    (University of Edinburgh)

  • Kamil R. Kranc

    (Queen Mary University of London
    University of Edinburgh)

  • Maria Christophorou

    (University of Cambridge)

  • Erika L. Pearce

    (Max Planck Institute of Immunobiology and Epigenetics
    Johns Hopkins University)

  • Ingo Ringshausen

    (University of Cambridge)

  • Andrew J. Finch

    (University of Edinburgh
    Queen Mary University of London)

Abstract

The MYC oncogene is a potent driver of growth and proliferation but also sensitises cells to apoptosis, which limits its oncogenic potential. MYC induces several biosynthetic programmes and primary cells overexpressing MYC are highly sensitive to glutamine withdrawal suggesting that MYC-induced sensitisation to apoptosis may be due to imbalance of metabolic/energetic supply and demand. Here we show that MYC elevates global transcription and translation, even in the absence of glutamine, revealing metabolic demand without corresponding supply. Glutamine withdrawal from MRC-5 fibroblasts depletes key tricarboxylic acid (TCA) cycle metabolites and, in combination with MYC activation, leads to AMP accumulation and nucleotide catabolism indicative of energetic stress. Further analyses reveal that glutamine supports viability through TCA cycle energetics rather than asparagine biosynthesis and that TCA cycle inhibition confers tumour suppression on MYC-driven lymphoma in vivo. In summary, glutamine supports the viability of MYC-overexpressing cells through an energetic rather than a biosynthetic mechanism.

Suggested Citation

  • Joy Edwards-Hicks & Huizhong Su & Maurizio Mangolini & Kubra K. Yoneten & Jimi Wills & Giovanny Rodriguez-Blanco & Christine Young & Kevin Cho & Heather Barker & Morwenna Muir & Ania Naila Guerrieri &, 2022. "MYC sensitises cells to apoptosis by driving energetic demand," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32368-z
    DOI: 10.1038/s41467-022-32368-z
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    References listed on IDEAS

    as
    1. Natividad Gomez-Roman & Carla Grandori & Robert N. Eisenman & Robert J. White, 2003. "Direct activation of RNA polymerase III transcription by c-Myc," Nature, Nature, vol. 421(6920), pages 290-294, January.
    2. Edward T. Chouchani & Victoria R. Pell & Edoardo Gaude & Dunja Aksentijević & Stephanie Y. Sundier & Ellen L. Robb & Angela Logan & Sergiy M. Nadtochiy & Emily N. J. Ord & Anthony C. Smith & Filmon Ey, 2014. "Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS," Nature, Nature, vol. 515(7527), pages 431-435, November.
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