Cancer cells depend on environmental lipids for proliferation when electron acceptors are limited.
Cancer cells depend on environmental lipids for proliferation when electron acceptors are limited.
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DOI：
10.1038/s42255-022-00588-8
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发表时间：
2022-06
影响因子：
20.8
通讯作者：
Vitkup, Dennis
中科院分区：
文献类型：
--
作者：
Li, Zhaoqi;Ji, Brian W.;Dixit, Purushottam D.;Tchourine, Konstantine;Lien, Evan C.;Hosios, Aaron M.;Abbott, Keene L.;Rutter, Justine C.;Westermark, Anna M.;Gorodetsky, Elizabeth F.;Sullivan, Lucas B.;Vander Heiden, Matthew G.;Vitkup, Dennis
需要辅因子NAD+再生的氧化生物质的产生可能是受环境条件影响的增殖瓶颈。然而，目前缺乏对可能受NAD+缺乏影响的代谢过程的全面定量了解。在这里，我们使用计算和实验方法来证明，除了需要氧气的脂质去饱和反应，从头脂质生物合成可以施加大量的NAD+消耗成本增殖癌细胞。我们的研究结果表明，当电子受体是有限的，环境脂质成为至关重要的增殖，因为NAD+是必需的脂肪酸生物合成产生的前体。我们发现，脂肪生成柠檬酸盐合成的氧化和甚至净还原途径都是由依赖于NAD+可用性的反应门控的。我们还表明，获得乙酸可以缓解脂质营养缺陷型绕过NAD+消耗反应参与从头脂质合成。与生物化学结果一致，不同肿瘤类型的基因表达分析表明，脂质生物合成与缺氧标志物的表达密切相关，而脂质摄取基因在缺氧中始终上调。总的来说，我们的研究结果定义了氧化代谢的要求，以支持从头脂质生物合成，并提供了一个机械解释的癌细胞依赖于脂质摄取的电子受体有限的条件下，如缺氧。
Production of oxidized biomass, which requires regeneration of the cofactor NAD+, can be a proliferation bottleneck that is influenced by environmental conditions. However, a comprehensive quantitative understanding of metabolic processes that may be affected by NAD+ deficiency is currently missing. Here, we use computational and experimental approaches to demonstrate that in addition to requiring oxygen for lipid desaturation reactions, de novo lipid biosynthesis can impose a substantial NAD+ consumption cost in proliferating cancer cells. Our results reveal that when electron acceptors are limited environmental lipids become crucial for proliferation because NAD+ is required to generate precursors for fatty acid biosynthesis. We find that both oxidative and even net reductive pathways for lipogenic citrate synthesis are gated by reactions that depend on NAD+ availability. We also show that access to acetate can relieve lipid auxotrophy by bypassing the NAD+ consuming reactions involved in de novo lipid synthesis. Consistent with biochemical results, analysis of gene expression across diverse tumor types demonstrates that lipid biosynthesis strongly anticorrelates with expression of hypoxia markers, whereas lipid uptake genes are consistently upregulated in hypoxia. Overall, our results define a requirement for oxidative metabolism to support de novo lipid biosynthesis and provide a mechanistic explanation for cancer cell dependence on lipid uptake in electron acceptors limited conditions such as hypoxia.
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影响因子：
82.9
作者：
Davidson SM;Jonas O;Keibler MA;Hou HW;Luengo A;Mayers JR;Wyckoff J;Del Rosario AM;Whitman M;Chin CR;Condon KJ;Lammers A;Kellersberger KA;Stall BK;Stephanopoulos G;Bar-Sagi D;Han J;Rabinowitz JD;Cima MJ;Langer R;Vander Heiden MG
通讯作者：
Vander Heiden MG
影响因子：
25
作者：
Dietrich, Marcelo O.;Bober, Jeremy;Horvath, Tamas L.
通讯作者：
Horvath, Tamas L.
DOI：
10.1111/j.1432-1033.1972.tb01840.x
发表时间：
1972-01-01
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
BUCHER, T;BRAUSER, B;KLEIN, F
通讯作者：
KLEIN, F
影响因子：
64.5
作者：
Faubert B;Li KY;Cai L;Hensley CT;Kim J;Zacharias LG;Yang C;Do QN;Doucette S;Burguete D;Li H;Huet G;Yuan Q;Wigal T;Butt Y;Ni M;Torrealba J;Oliver D;Lenkinski RE;Malloy CR;Wachsmann JW;Young JD;Kernstine K;DeBerardinis RJ
通讯作者：
DeBerardinis RJ
DOI：
10.1073/pnas.0610772104
发表时间：
2007-02-06
影响因子：
11.1
作者：
Duarte, Natalie C.;Becker, Scott A.;Palsson, Bernhard O.
通讯作者：
Palsson, Bernhard O.