Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Crewe Road South, Edinburgh, EH4 2XR, UK.
Department of Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Stübeweg 51, D-79108, Freiburg, Germany.
Nat Commun. 2022 Aug 9;13(1):4674. doi: 10.1038/s41467-022-32368-z.
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.
MYC 癌基因是生长和增殖的强大驱动因素，但也使细胞对细胞凋亡敏感，从而限制了其致癌潜力。MYC 诱导几种生物合成程序，并且过表达 MYC 的原代细胞对谷氨酰胺缺乏非常敏感，这表明 MYC 诱导的细胞凋亡敏感性可能是由于代谢/能量供应和需求的不平衡。在这里，我们表明 MYC 即使在没有谷氨酰胺的情况下也能提高全局转录和翻译水平，从而揭示了没有相应供应的代谢需求。从 MRC-5 成纤维细胞中去除谷氨酰胺会耗尽关键的三羧酸 (TCA) 循环代谢物，并且与 MYC 激活相结合，会导致 AMP 积累和核苷酸分解代谢，表明存在能量应激。进一步的分析表明，谷氨酰胺通过 TCA 循环能量而不是天冬酰胺生物合成来支持细胞活力，并且 TCA 循环抑制在体内赋予 MYC 驱动的淋巴瘤肿瘤抑制作用。总之，谷氨酰胺通过能量而不是生物合成机制来支持过表达 MYC 的细胞的活力。
