TY - JOUR
T1 - MYC sensitises cells to apoptosis by driving energetic demand
AU - Edwards-Hicks, Joy
AU - Su, Huizhong
AU - Mangolini, Maurizio
AU - Yoneten, Kubra K.
AU - Wills, Jimi
AU - Rodriguez-Blanco, Giovanny
AU - Young, Christine
AU - Cho, Kevin
AU - Barker, Heather
AU - Muir, Morwenna
AU - Guerrieri, Ania Naila
AU - Li, Xue Feng
AU - White, Rachel
AU - Manasterski, Piotr
AU - Mandrou, Elena
AU - Wills, Karen
AU - Chen, Jingyu
AU - Abraham, Emily
AU - Sateri, Kianoosh
AU - Qian, Bin Zhi
AU - Bankhead, Peter
AU - Arends, Mark
AU - Gammoh, Noor
AU - von Kriegsheim, Alex
AU - Patti, Gary J.
AU - Sims, Andrew H.
AU - Acosta, Juan Carlos
AU - Brunton, Valerie
AU - Kranc, Kamil R.
AU - Christophorou, Maria
AU - Pearce, Erika L.
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 - 2022/12
Y1 - 2022/12
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/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.
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/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.
UR - http://www.scopus.com/inward/record.url?scp=85135732087&partnerID=8YFLogxK
U2 - 10.1038/s41467-022-32368-z
DO - 10.1038/s41467-022-32368-z
M3 - Article
C2 - 35945217
AN - SCOPUS:85135732087
SN - 2041-1723
VL - 13
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 4674
ER -