Aspartate is a limiting metabolite for cancer cell proliferation under hypoxia and in tumours.
Aspartate is a limiting metabolite for cancer cell proliferation under hypoxia and in tumours.
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DOI：
10.1038/s41556-018-0118-z
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发表时间：
2018-07
影响因子：
21.3
通讯作者：
Birsoy K
中科院分区：
文献类型：
--
作者：
Garcia-Bermudez J;Baudrier L;La K;Zhu XG;Fidelin J;Sviderskiy VO;Papagiannakopoulos T;Molina H;Snuderl M;Lewis CA;Possemato RL;Birsoy K
由于氧气是许多代谢途径所必需的，肿瘤缺氧可能会损害癌细胞增殖。然而，在缺氧和肿瘤中限制增殖的代谢物是未知的。在这里，我们评估了一组癌细胞在抑制线粒体电子传递链（ETC）（一种需要分子氧的主要代谢途径）后的增殖。对ETC抑制的敏感性在细胞系中各不相同，随后的代谢组学分析发现天冬氨酸可用性是敏感性的主要决定因素。对ETC抑制最不敏感的细胞系通过天冬氨酸/谷氨酸转运蛋白SLC 1A 3输入天冬氨酸水平。SLC 1A 3活性的遗传或药理学调节显著改变了癌细胞对ETC抑制剂的敏感性。有趣的是，天冬氨酸水平在低氧下也会降低，并且通过SLC 1A 3增加天冬氨酸输入为低氧水平和肿瘤异种移植物中的癌细胞提供了竞争优势。最后，原发性人类肿瘤中的天冬氨酸水平与缺氧标志物的表达呈负相关，表明肿瘤缺氧足以抑制ETC，从而抑制体内天冬氨酸合成。因此，天冬氨酸可能是肿瘤生长的限制性代谢物，天冬氨酸的可用性可能是癌症治疗的目标。
As oxygen is essential for many metabolic pathways, tumor hypoxia may impair cancer cell proliferation. However, the limiting metabolites for proliferation under hypoxia and in tumors are unknown. Here, we assessed proliferation of a collection of cancer cells upon inhibition of the mitochondrial electron transport chain (ETC), a major metabolic pathway requiring molecular oxygen. Sensitivity to ETC inhibition varied across cell lines, and subsequent metabolomic analysis uncovered aspartate availability as a major determinant of sensitivity. Cell lines least sensitive to ETC inhibition maintain aspartate levels by importing it through an aspartate/glutamate transporter, SLC1A3. Genetic or pharmacologic modulation of SLC1A3 activity markedly altered cancer cell sensitivity to ETC inhibitors. Interestingly, aspartate levels also decrease under low oxygen, and increasing aspartate import by SLC1A3 provides a competitive advantage to cancer cells at low oxygen levels and in tumor xenografts. Finally, aspartate levels in primary human tumors negatively correlate with the expression of hypoxia markers, suggesting that tumor hypoxia is sufficient to inhibit ETC and, consequently, aspartate synthesis in vivo. Therefore, aspartate may be a limiting metabolite for tumor growth and aspartate availability could be targeted for cancer therapy.
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癌细胞对葡萄糖限制和双胍类药物敏感性的代谢决定因素。
影响因子：
64.8
作者：
Birsoy, Kivanc;Possemato, Richard;Lorbeer, Franziska K.;Bayraktar, Erol C.;Thiru, Prathapan;Yucel, Burcu;Wang, Tim;Chen, Walter W.;Clish, Clary B.;Sabatini, David M.
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Sabatini, David M.
影响因子：
3.7
作者：
Frezza C;Zheng L;Tennant DA;Papkovsky DB;Hedley BA;Kalna G;Watson DG;Gottlieb E
通讯作者：
Gottlieb E
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：
29
作者：
Pavlova NN;Thompson CB
通讯作者：
Thompson CB
影响因子：
19
作者：
Ackerman, Daniel;Simon, M. Celeste
通讯作者：
Simon, M. Celeste