MYC sensitises cells to apoptosis by driving energetic demand

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, Xue-Feng Li, Rachel White, Piotr Manasterski, Elena Mandrou, Karen Wills, Jingyu Chen, Emily Abraham, Kianoosh Sateri, Bin-Zhi Qian, Peter Bankhead, Mark Arends, Noor Gammoh, Alex von Kriegsheim, Gary J. Patti, Andrew H. Sims, Juan Carlos Acosta, Valerie Brunton, Kamil R. Kranc, Maria Christophorou, Erika L. Pearce, Ingo Ringshausen and Andrew J. Finch ()
Additional contact information
Joy Edwards-Hicks: University of Edinburgh
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
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
Valerie Brunton: University of Edinburgh
Kamil R. Kranc: Queen Mary University of London
Maria Christophorou: University of Cambridge
Erika L. Pearce: Max Planck Institute of Immunobiology and Epigenetics
Ingo Ringshausen: University of Cambridge
Andrew J. Finch: University of Edinburgh

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-32368-z

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