Lactate Reprograms Energy and Lipid Metabolism in Glucose-Deprived Oxidative Glioma Stem Cells.
Lactate Reprograms Energy and Lipid Metabolism in Glucose-Deprived Oxidative Glioma Stem Cells.
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DOI：
10.3390/metabo11050325
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发表时间：
2021-05-18
期刊：
影响因子：
4.1
通讯作者：
Sampetrean O
中科院分区：
文献类型：
--
作者：
Minami N;Tanaka K;Sasayama T;Kohmura E;Saya H;Sampetrean O
快速生长的肿瘤通过用替代碳源补充葡萄糖来满足其生物能量需求。癌症干细胞是恶性肿瘤中最多功能和最强大的细胞。它们通过灵活地重新编程相关途径来避免潜在的致命代谢和其他类型的压力，但目前尚不清楚替代碳源是否对维持它们的肿瘤传播能力很重要。在这里，我们评估了糖酵解和氧化小鼠胶质瘤干细胞（GSC）在超低葡萄糖培养基中生长的能力。球体形成试验表明，外源性乳酸盐和乙酸盐逆转了在这种培养基中氧化GSC的生长障碍。细胞外通量分析表明，乳酸支持这些细胞中的耗氧量，而代谢组学分析表明，它增加了细胞内的三羧酸循环中间体，ATP和GTP的水平，以及增加腺苷酸和鸟苷酸电荷。乳酸还逆转了葡萄糖剥夺细胞中明显的胆碱消耗以及重编程磷脂和脂肪酸生物合成。这种代谢重编程与乳酸盐处理的GSC形成的更具侵袭性的颅内肿瘤表型相关。因此，我们的研究结果表明，乳酸是一个重要的替代能源和生物合成底物的氧化GSC，它维持他们的生长条件下的葡萄糖剥夺。
Fast-growing tumors satisfy their bioenergetic needs by supplementing glucose with alternative carbon sources. Cancer stem cells are the most versatile and robust cells within malignant tumors. They avoid potentially lethal metabolic and other types of stress through flexible reprogramming of relevant pathways, but it has remained unclear whether alternative carbon sources are important for the maintenance of their tumor-propagating ability. Here we assessed the ability of glycolytic and oxidative murine glioma stem cells (GSCs) to grow in an ultralow glucose medium. Sphere formation assays revealed that exogenous lactate and acetate reversed the growth impairment of oxidative GSCs in such medium. Extracellular flux analysis showed that lactate supported oxygen consumption in these cells, whereas metabolomics analysis revealed that it increased the intracellular levels of tricarboxylic acid cycle intermediates, ATP, and GTP as well as increased adenylate and guanylate charge. Lactate also reversed the depletion of choline apparent in the glucose-deprived cells as well as reprogrammed phospholipid and fatty acid biosynthesis. This metabolic reprogramming was associated with a more aggressive phenotype of intracranial tumors formed by lactate-treated GSCs. Our results thus suggest that lactate is an important alternative energetic and biosynthetic substrate for oxidative GSCs, and that it sustains their growth under conditions of glucose deprivation.
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影响因子：
29
作者：
Liu L;MacKenzie KR;Putluri N;Maletić-Savatić M;Bellen HJ
通讯作者：
Bellen HJ
影响因子：
23.9
作者：
Lagadinou, Eleni D.;Sach, Alexander;Callahan, Kevin;Rossi, Randall M.;Neering, Sarah J.;Minhajuddin, Mohammad;Ashton, John M.;Pei, Shanshan;Grose, Valerie;O'Dwyer, Kristen M.;Liesveld, Jane L.;Brookes, Paul S.;Becker, Michael W.;Jordan, Craig T.
通讯作者：
Jordan, Craig T.
影响因子：
14.8
作者：
Chen YJ;Mahieu NG;Huang X;Singh M;Crawford PA;Johnson SL;Gross RW;Schaefer J;Patti GJ
通讯作者：
Patti GJ
影响因子：
--
作者：
Ohashi, Yoshiaki;Hirayama, Akiyoshi;Soga, Tomoyoshi
通讯作者：
Soga, Tomoyoshi
Nanog通过氧化磷酸化和脂肪酸代谢的肿瘤性变化来代谢重新编程肿瘤发射类样细胞。
影响因子：
29
作者：
Chen CL;Uthaya Kumar DB;Punj V;Xu J;Sher L;Tahara SM;Hess S;Machida K
通讯作者：
Machida K