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 QianPeter 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, Andrew J. Finch

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

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.

Original languageEnglish
Article number4674
JournalNature communications
Volume13
Issue number1
DOIs
StatePublished - Dec 2022

Fingerprint

Dive into the research topics of 'MYC sensitises cells to apoptosis by driving energetic demand'. Together they form a unique fingerprint.

Cite this