MYC sensitises cells to apoptosis by driving energetic demand
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Published:2022-08-09
Issue:1
Volume:13
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Edwards-Hicks JoyORCID, Su Huizhong, Mangolini Maurizio, Yoneten Kubra K., Wills JimiORCID, Rodriguez-Blanco Giovanny, Young Christine, Cho KevinORCID, Barker Heather, Muir Morwenna, Guerrieri Ania NailaORCID, Li Xue-Feng, White Rachel, Manasterski Piotr, Mandrou ElenaORCID, Wills Karen, Chen Jingyu, Abraham Emily, Sateri Kianoosh, Qian Bin-ZhiORCID, Bankhead PeterORCID, Arends MarkORCID, Gammoh NoorORCID, von Kriegsheim AlexORCID, Patti Gary J.ORCID, Sims Andrew H.ORCID, Acosta Juan CarlosORCID, Brunton Valerie, Kranc Kamil R.ORCID, Christophorou MariaORCID, Pearce Erika L.ORCID, Ringshausen IngoORCID, Finch Andrew J.ORCID
Abstract
AbstractThe 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.
Funder
RCUK | Medical Research Council Cancer Research UK Wellcome Trust Barts Charity
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
Reference60 articles.
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