MYC sensitises cells to apoptosis by driving energetic demand

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 an 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 depleted key TCA cycle metabolites and, in combination with MYC activation, led to AMP accumulation and nucleotide catabolism indicative of energetic stress. Further analyses revealed 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.