Physiologic Medium Rewires Cellular Metabolism and Reveals Uric Acid as an Endogenous Inhibitor of UMP Synthase.
Physiologic Medium Rewires Cellular Metabolism and Reveals Uric Acid as an Endogenous Inhibitor of UMP Synthase.
复制标题
DOI：
10.1016/j.cell.2017.03.023
复制
发表时间：
2017-04-06
期刊：
影响因子：
64.5
通讯作者：
Sabatini DM
中科院分区：
文献类型：
--
作者：
Cantor JR;Abu-Remaileh M;Kanarek N;Freinkman E;Gao X;Louissaint A Jr;Lewis CA;Sabatini DM
环境因素的复杂相互作用影响人类细胞的代谢，但无论是传统培养基还是小鼠血浆都无法模拟人类血浆的代谢物组成。在这里，我们开发了一种极性代谢物浓度与人血浆相当的培养基（人血浆样培养基；HPLM）。与传统培养基相比，在HPLM中培养对细胞代谢有广泛的影响，包括代谢组、氧化还原状态和葡萄糖利用。其中最突出的是对新生嘧啶合成的抑制作用——这种作用可以追溯到尿酸，人类血液中的尿酸比老鼠和其他非灵长类动物高10倍。我们发现尿酸直接抑制UMP合成酶，从而降低癌细胞对化疗药物5-氟尿嘧啶的敏感性。因此，能够更好地概括人体血浆组成的介质揭示了不可预见的代谢线路和调节，这表明HPLM应该具有广泛的用途。在培养中模拟人血浆代谢物组成揭示了新的肿瘤特异性责任和代谢物-药物相互作用
A complex interplay of environmental factors impacts the metabolism of human cells, but neither traditional culture media nor mouse plasma mimic the metabolite composition of human plasma. Here, we developed a culture medium with polar metabolite concentrations comparable to those of human plasma (human plasma-like medium; HPLM). Culture in HPLM, relative to that in traditional media, had widespread effects on cellular metabolism, including on the metabolome, redox state, and glucose utilization. Among the most prominent is an inhibition of de novo pyrimidine synthesis – an effect traced to uric acid, which is 10-fold higher in the blood of humans than of mice and other non-primates. We find that uric acid directly inhibits UMP synthase and consequently reduces the sensitivity of cancer cells to the chemotherapeutic agent 5-fluorouracil. Thus, media that better recapitulates the composition of human plasma reveals unforeseen metabolic wiring and regulation, suggesting that HPLM should be of broad utility. Mimicking the metabolite composition of human plasma in culture reveals new tumor specific liabilities and metabolite-drug interactions