IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-32368-z.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-32368-z
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-022-32368-z?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    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.
    3. Susanne Walz & Francesca Lorenzin & Jennifer Morton & Katrin E. Wiese & Björn von Eyss & Steffi Herold & Lukas Rycak & Hélène Dumay-Odelot & Saadia Karim & Marek Bartkuhn & Frederik Roels & Torsten Wü, 2014. "Correction: Corrigendum: Activation and repression by oncogenic MYC shape tumour-specific gene expression profiles," Nature, Nature, vol. 516(7531), pages 440-440, December.
    4. Susanne Walz & Francesca Lorenzin & Jennifer Morton & Katrin E. Wiese & Björn von Eyss & Steffi Herold & Lukas Rycak & Hélène Dumay-Odelot & Saadia Karim & Marek Bartkuhn & Frederik Roels & Torsten Wü, 2014. "Activation and repression by oncogenic MYC shape tumour-specific gene expression profiles," Nature, Nature, vol. 511(7510), pages 483-487, July.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Nicole M. Sodir & Luca Pellegrinet & Roderik M. Kortlever & Tania Campos & Yong-Won Kwon & Shinseog Kim & Daniel Garcia & Alessandra Perfetto & Panayiotis Anastasiou & Lamorna Brown Swigart & Mark J. , 2022. "Reversible Myc hypomorphism identifies a key Myc-dependency in early cancer evolution," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    2. Yu Jin Chung & Zoe Hoare & Friedrich Baark & Chak Shun Yu & Jia Guo & William Fuller & Richard Southworth & Doerthe M. Katschinski & Michael P. Murphy & Thomas R. Eykyn & Michael J. Shattock, 2024. "Elevated Na is a dynamic and reversible modulator of mitochondrial metabolism in the heart," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    3. Thomas Agius & Raffaella Emsley & Arnaud Lyon & Michael R. MacArthur & Kevin Kiesworo & Anna Faivre & Louis Stavart & Martine Lambelet & David Legouis & Sophie Seigneux & Déla Golshayan & Francois Laz, 2024. "Short-term hypercaloric carbohydrate loading increases surgical stress resilience by inducing FGF21," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    4. Chris G. Faulkes & Thomas R. Eykyn & Jan Lj. Miljkovic & James D. Gilbert & Rebecca L. Charles & Hiran A. Prag & Nikayla Patel & Daniel W. Hart & Michael P. Murphy & Nigel C. Bennett & Dunja Aksentije, 2024. "Naked mole-rats have distinctive cardiometabolic and genetic adaptations to their underground low-oxygen lifestyles," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    5. Maithily S. Nanadikar & Ana M. Vergel Leon & Jia Guo & Gijsbert J. Belle & Aline Jatho & Elvina S. Philip & Astrid F. Brandner & Rainer A. Böckmann & Runzhu Shi & Anke Zieseniss & Carla M. Siemssen & , 2023. "IDH3γ functions as a redox switch regulating mitochondrial energy metabolism and contractility in the heart," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    6. Jiayi Wang & Mengke Zhao & Meina Wang & Dong Fu & Lin Kang & Yu Xu & Liming Shen & Shilin Jin & Liang Wang & Jing Liu, 2024. "Human neural stem cell-derived artificial organelles to improve oxidative phosphorylation," Nature Communications, Nature, vol. 15(1), pages 1-24, December.
    7. Xiaoduo Tang & Jingyan Ren & Xin Wei & Tao Wang & Haiqiu Li & Yihan Sun & Yang Liu & Mingli Chi & Shoujun Zhu & Laijin Lu & Junhu Zhang & Bai Yang, 2023. "Exploiting synergistic effect of CO/NO gases for soft tissue transplantation using a hydrogel patch," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    8. Masataka Kawamura & Catherine Parmentier & Samrat Ray & Sergi Clotet-Freixas & Sharon Leung & Rohan John & Laura Mazilescu & Emmanuel Nogueira & Yuki Noguchi & Toru Goto & Bhranavi Arulratnam & Sujani, 2024. "Normothermic ex vivo kidney perfusion preserves mitochondrial and graft function after warm ischemia and is further enhanced by AP39," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    9. Xueqiang Wang & Xing Zhang & Ke Cao & Mengqi Zeng & Xuyang Fu & Adi Zheng & Feng Zhang & Feng Gao & Xuan Zou & Hao Li & Min Li & Weiqiang Lv & Jie Xu & Jiangang Long & Weijin Zang & Jinghai Chen & Fen, 2022. "Cardiac disruption of SDHAF4-mediated mitochondrial complex II assembly promotes dilated cardiomyopathy," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    10. Pankaj Sharma & Elena Maklashina & Markus Voehler & Sona Balintova & Sarka Dvorakova & Michal Kraus & Katerina Hadrava Vanova & Zuzana Nahacka & Renata Zobalova & Stepana Boukalova & Kristyna Cunatova, 2024. "Disordered-to-ordered transitions in assembly factors allow the complex II catalytic subunit to switch binding partners," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    11. John O. Onukwufor & M. Arsalan Farooqi & Anežka Vodičková & Shon A. Koren & Aksana Baldzizhar & Brandon J. Berry & Gisela Beutner & George A. Porter & Vsevolod Belousov & Alan Grossfield & Andrew P. W, 2022. "A reversible mitochondrial complex I thiol switch mediates hypoxic avoidance behavior in C. elegans," Nature Communications, Nature, vol. 13(1), pages 1-14, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32368-z. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.