Myc sensitises cells to apoptosis by driving energetic demand

Joy Edwards-Hicks; Huizhong Su; Maurizio Mangolini; Kubra Karaosmanoglu Yoneten; Jimi Wills; Giovanny Rodriguez Blanco; Christine Young; Kevin Cho; Heather Barker; Morwenna Muir; Ania Guerrieri; Xue-Feng Li; Rachel White; Piotr Manasterski; Eena Mandrou; Karen Wills; Jingyu Chen; Emily Abraham; Kianoosh Sateri; Bin-Zhi Qian; Peter Bankhead; Mark J Arends; Noor Gammoh; Alexander von Kriegsheim; Gary Patti; Andrew H Sims; Juan Carlos Acosta; Valerie G Brunton; Kamil R Kranc; Maria A Christophorou; Erika Pearce; Ingo Ringshausen; Andrew J Finch

doi:10.1038/s41467-022-32368-z

Myc sensitises cells to apoptosis by driving energetic demand

Joy Edwards-Hicks, Huizhong Su, Maurizio Mangolini, Kubra Karaosmanoglu Yoneten, Jimi Wills, Giovanny Rodriguez Blanco, Christine Young, Kevin Cho, Heather Barker, Morwenna Muir, Ania Guerrieri, Xue-Feng Li, Rachel White, Piotr Manasterski, Eena Mandrou, Karen Wills, Jingyu Chen, Emily Abraham, Kianoosh Sateri, Bin-Zhi QianPeter Bankhead, Mark J Arends, Noor Gammoh, Alexander von Kriegsheim, Gary Patti, Andrew H Sims, Juan Carlos Acosta, Valerie G Brunton, Kamil R Kranc, Maria A Christophorou, Erika Pearce, Ingo Ringshausen, Andrew J Finch^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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 language	English
Journal	Nature Communications
Early online date	9 Aug 2022
DOIs	https://doi.org/10.1038/s41467-022-32368-z
Publication status	E-pub ahead of print - 9 Aug 2022

Keywords / Materials (for Non-textual outputs)

MYC
apoptosis
glutamine
energy
adenylate kinase
nucleotide catabolism,
nucleotide biosynthesis
pentose phosphate pathway
metabolic fix

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Myc sensitises cells to apoptosis by driving energetic demand-finalFinal published version, 2.37 MB

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Edwards-Hicks, J., Su, H., Mangolini, M., Karaosmanoglu Yoneten, K., Wills, J., Rodriguez Blanco, G., Young, C., Cho, K., Barker, H., Muir, M., Guerrieri, A., Li, X.-F., White, R., Manasterski, P., Mandrou, E., Wills, K., Chen, J., Abraham, E., Sateri, K., ... Finch, A. J. (2022). Myc sensitises cells to apoptosis by driving energetic demand. Nature Communications. Advance online publication. https://doi.org/10.1038/s41467-022-32368-z

@article{844de4d1e15b498384388391452dca34,

title = "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/energeticsupply 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 viabilitythrough 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.",

keywords = "MYC, apoptosis, glutamine, energy, adenylate kinase, nucleotide catabolism,, nucleotide biosynthesis, pentose phosphate pathway, metabolic fix",

author = "Joy Edwards-Hicks and Huizhong Su and Maurizio Mangolini and {Karaosmanoglu Yoneten}, Kubra and Jimi Wills and {Rodriguez Blanco}, Giovanny and Christine Young and Kevin Cho and Heather Barker and Morwenna Muir and Ania Guerrieri and Xue-Feng Li and Rachel White and Piotr Manasterski and Eena Mandrou and Karen Wills and Jingyu Chen and Emily Abraham and Kianoosh Sateri and Bin-Zhi Qian and Peter Bankhead and Arends, {Mark J} and Noor Gammoh and {von Kriegsheim}, Alexander and Gary Patti and Sims, {Andrew H} and Acosta, {Juan Carlos} and Brunton, {Valerie G} and Kranc, {Kamil R} and Christophorou, {Maria A} and Erika Pearce and Ingo Ringshausen and Finch, {Andrew J}",

note = "Funding Information: We thank colleagues in the IGMM, particularly Nick Hastie, for helpful discussions and criticisms of the manuscript. Work in the A.J.F. lab was supported by Barts Charity (MGU0404 to Nick Lemoine), The Wellcome Trust (WT-ISSF), the Melville Trust and a Cancer Research UK Centre Grant to Barts Cancer Institute (C355/A25137). AHS is very grateful for funding from Breast Cancer Now. J.E.H. was funded by a studentship from the Medical Research Council. J.C.A. was funded by a Career Development Fellowship from Cancer Research UK (C47559/A16243). I.R. was funded by a Senior Clinical Fellowship from Cancer Research UK (C49940/A17480). Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = aug,

day = "9",

doi = "10.1038/s41467-022-32368-z",

language = "English",

journal = "Nature Communications",

issn = "2041-1723",

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Edwards-Hicks, J, Su, H, Mangolini, M, Karaosmanoglu Yoneten, K, Wills, J, Rodriguez Blanco, G, Young, C, Cho, K, Barker, H , Muir, M, Guerrieri, A, Li, X-F, White, R, Manasterski, P, Mandrou, E, Wills, K, Chen, J, Abraham, E, Sateri, K, Qian, B-Z, Bankhead, P , Arends, MJ , Gammoh, N , von Kriegsheim, A, Patti, G, Sims, AH, Acosta, JC , Brunton, VG, Kranc, KR, Christophorou, MA, Pearce, E, Ringshausen, I & Finch, AJ 2022, 'Myc sensitises cells to apoptosis by driving energetic demand', Nature Communications. https://doi.org/10.1038/s41467-022-32368-z

TY - JOUR

T1 - Myc sensitises cells to apoptosis by driving energetic demand

AU - Edwards-Hicks, Joy

AU - Su, Huizhong

AU - Mangolini, Maurizio

AU - Karaosmanoglu Yoneten, Kubra

AU - Wills, Jimi

AU - Rodriguez Blanco, Giovanny

AU - Young, Christine

AU - Cho, Kevin

AU - Barker, Heather

AU - Muir, Morwenna

AU - Guerrieri, Ania

AU - Li, Xue-Feng

AU - White, Rachel

AU - Manasterski, Piotr

AU - Mandrou, Eena

AU - Wills, Karen

AU - Chen, Jingyu

AU - Abraham, Emily

AU - Sateri, Kianoosh

AU - Qian, Bin-Zhi

AU - Bankhead, Peter

AU - Arends, Mark J

AU - Gammoh, Noor

AU - von Kriegsheim, Alexander

AU - Patti, Gary

AU - Sims, Andrew H

AU - Acosta, Juan Carlos

AU - Brunton, Valerie G

AU - Kranc, Kamil R

AU - Christophorou, Maria A

AU - Pearce, Erika

AU - Ringshausen, Ingo

AU - Finch, Andrew J

N1 - Funding Information: We thank colleagues in the IGMM, particularly Nick Hastie, for helpful discussions and criticisms of the manuscript. Work in the A.J.F. lab was supported by Barts Charity (MGU0404 to Nick Lemoine), The Wellcome Trust (WT-ISSF), the Melville Trust and a Cancer Research UK Centre Grant to Barts Cancer Institute (C355/A25137). AHS is very grateful for funding from Breast Cancer Now. J.E.H. was funded by a studentship from the Medical Research Council. J.C.A. was funded by a Career Development Fellowship from Cancer Research UK (C47559/A16243). I.R. was funded by a Senior Clinical Fellowship from Cancer Research UK (C49940/A17480). Publisher Copyright: © 2022, The Author(s).

PY - 2022/8/9

Y1 - 2022/8/9

N2 - 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/energeticsupply 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 viabilitythrough 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.

AB - 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/energeticsupply 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 viabilitythrough 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.

KW - MYC

KW - apoptosis

KW - glutamine

KW - energy

KW - adenylate kinase

KW - nucleotide catabolism,

KW - nucleotide biosynthesis

KW - pentose phosphate pathway

KW - metabolic fix

U2 - 10.1038/s41467-022-32368-z

DO - 10.1038/s41467-022-32368-z

M3 - Article

SN - 2041-1723

JO - Nature Communications

JF - Nature Communications

ER -

Myc sensitises cells to apoptosis by driving energetic demand

Abstract

Keywords / Materials (for Non-textual outputs)

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