Identifying strategies to target the metabolic flexibility of tumours
Identifying strategies to target the metabolic flexibility of tumours
复制标题
确定针对肿瘤代谢灵活性的策略
DOI：
10.1038/s42255-020-0195-8
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发表时间：
2020-04-01
影响因子：
20.8
通讯作者：
Yuneva, Mariia
中科院分区：
文献类型：
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作者：
Mendez-Lucas, Andres;Lin, Wei;Yuneva, Mariia
癌症代谢的可塑性可能是有效靶向肿瘤特异性代谢脆弱性的主要障碍。在这里，我们确定的补偿机制后，抑制c-MYC诱导的肝肿瘤的中央碳代谢的主要途径。我们发现，虽然在肿瘤中抑制两种谷氨酰胺酶亚型（Gls 1和Gls 2）可显著延迟肿瘤发生，但由于酰胺基转移酶的作用，谷氨酰胺催化剂仍在继续。在体外和体内阻断谷氨酰胺催化剂和小鼠和人肿瘤细胞的增殖需要对谷氨酰胺酶和补偿性酰胺转移酶的协同抑制。Gls 1缺失也通过糖酵解得到补偿。因此，Gls 1和己糖激酶2的共抑制显著影响克雷布斯循环活性和肿瘤形成。最后，丝氨酸（Psat 1-KO）或脂肪酸（Fasn-KO）的生物合成的抑制通过循环营养素的摄取来补偿，并且丝氨酸和甘氨酸或脂肪酸两者的饮食限制协同抑制肿瘤发生。这些结果突出了肿瘤代谢的高度灵活性，并表明代谢补偿机制的药理学或饮食靶向可以改善治疗结果。
Plasticity of cancer metabolism can be a major obstacle to efficient targeting of tumour-specific metabolic vulnerabilities. Here, we identify the compensatory mechanisms following the inhibition of major pathways of central carbon metabolism in c-MYC-induced liver tumours. We find that, while inhibition of both glutaminase isoforms (Gls1 and Gls2) in tumours considerably delays tumourigenesis, glutamine catabolism continues, owing to the action of amidotransferases. Synergistic inhibition of both glutaminases and compensatory amidotransferases is required to block glutamine catabolism and proliferation of mouse and human tumour cells in vitro and in vivo. Gls1 deletion is also compensated for by glycolysis. Thus, co-inhibition of Gls1 and hexokinase 2 significantly affects Krebs cycle activity and tumour formation. Finally, the inhibition of biosynthesis of either serine (Psat1-KO) or fatty acid (Fasn-KO) is compensated for by uptake of circulating nutrients, and dietary restriction of both serine and glycine or fatty acids synergistically suppresses tumourigenesis. These results highlight the high flexibility of tumour metabolism and demonstrate that either pharmacological or dietary targeting of metabolic compensatory mechanisms can improve therapeutic outcomes.