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MYC sensitises cells to apoptosis by driving energetic demand

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

 Editorial: Nature Publishing Group

 Fecha de publicación: 09/08/2022

 Nº de páginas: 16

 Tipo de publicación: Artículo de Revista

 DOI: 10.1038/s41467-022-32368-z

 ISSN: 2041-1723

 Url de la publicación: https://doi.org/10.1038/s41467-022-32368-z

Autoría

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