Myc sensitises cells to apoptosis by driving energetic demand

Joy Edwards-Hicks, Huizhong Su, Maurizio Mangolini, Kubra Karaosmanoglu Yoneten, Jimi Wills, Giovanny Rodriguez Blanco, Christine Young, Kevin Cho, Heather Barker, Morwenna Muir, Ania Guerrieri, Xue-Feng Li, Rachel White, Piotr Manasterski, Eena Mandrou, Karen Wills, Jingyu Chen, Emily Abraham, Kianoosh Sateri, Bin-Zhi QianPeter Bankhead, Mark J Arends, Noor Gammoh, Alexander von Kriegsheim, Gary Patti, Andrew H Sims, Juan Carlos Acosta, Valerie G Brunton, Kamil R Kranc, Maria A Christophorou, Erika Pearce, Ingo Ringshausen, Andrew J Finch*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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.
Original languageEnglish
JournalNature Communications
Early online date9 Aug 2022
DOIs
Publication statusE-pub ahead of print - 9 Aug 2022

Keywords / Materials (for Non-textual outputs)

  • MYC
  • apoptosis
  • glutamine
  • energy
  • adenylate kinase
  • nucleotide catabolism,
  • nucleotide biosynthesis
  • pentose phosphate pathway
  • metabolic fix

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