MYC Sensitises Cells to Apoptosis by Driving Energetic Demand

Overview

Journal Nat Commun

Specialty Biology

Date 2022 Aug 9

PMID 35945217

Authors

Joy Edwards-Hicks

Huizhong Su

Maurizio Mangolini

Kubra K Yoneten

Jimi Wills

Giovanny Rodriguez-Blanco

Christine Young

Kevin Cho

Heather Barker

Morwenna Muir

Ania Naila Guerrieri

Xue-Feng Li

Rachel White

Piotr Manasterski

Elena Mandrou

Karen Wills

Jingyu Chen

Emily Abraham

Kianoosh Sateri

Bin-Zhi Qian

Peter Bankhead

Mark Arends

Noor Gammoh

Alex von Kriegsheim

Gary J Patti

Andrew H Sims

Juan Carlos Acosta

Valerie Brunton

Kamil R Kranc

Maria Christophorou

Erika L Pearce

Ingo Ringshausen

Andrew J Finch

Affiliations

Soon will be listed here.

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.

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