MYC sensitises cells to apoptosis by driving energetic demand.
MYC sensitises cells to apoptosis by driving energetic demand.
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DOI：
10.1038/s41467-022-32368-z
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发表时间：
2022-08-09
影响因子：
16.6
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中科院分区：
文献类型：
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作者：
MYC癌基因是生长和增殖的有力驱动因素，但也使细胞对凋亡敏感，这限制了其致癌潜力。MYC诱导几个生物合成程序和原代细胞过表达MYC是高度敏感的谷氨酰胺撤出表明MYC诱导的细胞凋亡的敏感性可能是由于代谢/能量供需失衡。在这里，我们表明，MYC提高全球转录和翻译，即使在没有谷氨酰胺，揭示代谢需求没有相应的供应。从MRC-5成纤维细胞中撤出谷氨酰胺会耗尽关键的三羧酸（TCA）循环代谢物，并与MYC激活相结合，导致AMP积累和指示能量应激的核苷酸催化剂。进一步的分析表明，谷氨酰胺通过TCA循环能量学而不是天冬酰胺生物合成来支持生存能力，并且TCA循环抑制在体内赋予对MYC驱动的淋巴瘤的肿瘤抑制。总之，谷氨酰胺通过能量机制而不是生物合成机制支持MYC过表达细胞的活力。MYC激活可使细胞在谷氨酰胺撤除后对凋亡敏感。在这里，作者表明MYC激活增强了全局转录和翻译，从而产生了代谢需求，而谷氨酰胺限制通过TCA能量的损失导致代谢需求和供应失衡，从而使细胞对凋亡敏感。
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 activation can sensitise cells to apoptosis upon glutamine withdrawal. Here the authors show that MYC activation enhances global transcription and translation that creates a metabolic demand, while glutamine limitation causes a metabolic demand and supply imbalance through loss of TCA energetics and thus, sensitises cells to apoptosis.
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影响因子：
--
作者：
Barfeld SJ;Fazli L;Persson M;Marjavaara L;Urbanucci A;Kaukoniemi KM;Rennie PS;Ceder Y;Chabes A;Visakorpi T;Mills IG
通讯作者：
Mills IG
影响因子：
50.3
作者：
Carroll PA;Diolaiti D;McFerrin L;Gu H;Djukovic D;Du J;Cheng PF;Anderson S;Ulrich M;Hurley JB;Raftery D;Ayer DE;Eisenman RN
通讯作者：
Eisenman RN
影响因子：
50.3
作者：
Finch, Andrew;Prescott, Julia;Evan, Gerard I.
通讯作者：
Evan, Gerard I.
影响因子：
21.3
作者：
Grewal, SS;Li, L;Edgar, BA
通讯作者：
Edgar, BA
影响因子：
8.8
作者：
Allen, Eric L.;Ulanet, Danielle B.;Smolen, Gromoslaw A.
通讯作者：
Smolen, Gromoslaw A.