Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells.
Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells.
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DOI：
10.1016/j.cmet.2011.12.009
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发表时间：
2012-01-04
期刊：
影响因子：
29
通讯作者：
Dang CV
中科院分区：
文献类型：
--
作者：
Le A;Lane AN;Hamaker M;Bose S;Gouw A;Barbi J;Tsukamoto T;Rojas CJ;Slusher BS;Zhang H;Zimmerman LJ;Liebler DC;Slebos RJ;Lorkiewicz PK;Higashi RM;Fan TW;Dang CV
由于MYC在许多人类癌症中起着因果作用，包括那些缺氧和营养不良的肿瘤微环境，我们已经确定了MYC诱导的人类伯基特淋巴瘤模型P493细胞系对有氧和缺氧条件以及葡萄糖剥夺的代谢反应，使用稳定同位素分解代谢组学。以[U-13C]-葡萄糖为示踪剂，MYC表达和缺氧增加了葡萄糖消耗和乳酸生成。以[U-13C，15N]-谷氨酰胺为示踪剂，在缺氧条件下，谷氨酰胺通过TCA循环的进口和代谢持续进行，谷氨酰胺对柠檬酸碳的贡献显著。在葡萄糖剥夺下，谷氨酰胺衍生的富马酸盐、苹果酸盐和柠檬酸盐显著增加。他们的13C标记模式证明了一种可替代的能量生成谷氨酰胺水解途径，涉及不依赖葡萄糖的TCA循环。谷氨酰胺代谢在缺氧和葡萄糖缺乏条件下的细胞存活和增殖中发挥重要作用，使其对谷氨酰胺酶抑制剂BPTES敏感，因此可能成为癌症治疗的靶点。
Because MYC plays a causal role in many human cancers, including those with hypoxic and nutrient-poor tumor microenvironments, we have determined the metabolic responses of a MYC-inducible human Burkitt lymphoma model P493 cell line to aerobic and hypoxic conditions, and to glucose deprivation, using Stable Isotope Resolved Metabolomics. Using [U-13C]-glucose as the tracer, both glucose consumption and lactate production were increased by MYC expression and hypoxia. Using [U-13C,15N]-glutamine as the tracer, glutamine import and metabolism through the TCA cycle persisted under hypoxia, and glutamine contributed significantly to citrate carbons. Under glucose deprivation, glutamine-derived fumarate, malate, and citrate were significantly increased. Their 13C labeling patterns demonstrate an alternative energy-generating glutaminolysis pathway involving a glucose-independent TCA cycle. The essential role of glutamine metabolism in cell survival and proliferation under hypoxia and glucose deficiency, makes them susceptible to the glutaminase inhibitor BPTES, and hence could be targeted for cancer therapy.
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影响因子：
3.6
作者：
Fan, Teresa W-M;Yuan, Peixiong;Lane, Andrew N.;Higashi, Richard M.;Wang, Yun;Hamidi, Anahita B.;Zhou, Rulun;Guitart, Xavier;Chen, Guang;Manji, Husseini K.;Kaddurah-Daouk, Rima
通讯作者：
Kaddurah-Daouk, Rima
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
11.2
作者：
Dang CV
通讯作者：
Dang CV
影响因子：
37.3
作者：
Fan TW;Lane AN;Higashi RM;Farag MA;Gao H;Bousamra M;Miller DM
通讯作者：
Miller DM
影响因子：
33.6
作者：
Goel S;Duda DG;Xu L;Munn LL;Boucher Y;Fukumura D;Jain RK
通讯作者：
Jain RK