MYC sensitises cells to apoptosis by driving energetic demand.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
09 08 2022
09 08 2022
Historique:
received:
16
02
2022
accepted:
27
07
2022
entrez:
9
8
2022
pubmed:
10
8
2022
medline:
12
8
2022
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 35945217
doi: 10.1038/s41467-022-32368-z
pii: 10.1038/s41467-022-32368-z
pmc: PMC9363429
doi:
Substances chimiques
Proto-Oncogene Proteins c-myc
0
Glutamine
0RH81L854J
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4674Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/P010008/2
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C49940/A17480
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C355/A25137
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_PC_17230
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C47559/A16243
Pays : United Kingdom
Informations de copyright
© 2022. The Author(s).
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