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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.
Fuente: Nature Communications (2022) 13:4674
Publisher: Nature Publishing Group
Publication date: 09/08/2022
No. of pages: 16
Publication type: Article
DOI: 10.1038/s41467-022-32368-z
ISSN: 2041-1723
Publication Url: https://doi.org/10.1038/s41467-022-32368-z
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EDWARDS-HICKS, JOY
SU, HUIZHONG
MANGOLINI, MAURIZIO
YONETEN, KUBRA K.
WILLS, JIMI
RODRÍGUEZ-BLANCO, GIOVANNY
YOUNG, CHRISTINE
CHO, KEVIN
BARKER, HEATHER
MUIR, MORWENNA
GUERRIERI, ANIA NAILA
LI, XUE-FENG
WHITE, RACHEL
MANASTERSKI, PIOTR
MANDROU, ELENA
WILLS, KAREN
CHEN, JINGYU
ABRAHAM, EMILY
SATERI, KIANOOSH
JUAN CARLOS ACOSTA COBACHO
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