A metabolic core model elucidates how enhanced utilization of glucose and glutamine, with enhanced glutamine-dependent lactate production, promotes cancer cell growth: The WarburQ effect.
A metabolic core model elucidates how enhanced utilization of glucose and glutamine, with enhanced glutamine-dependent lactate production, promotes cancer cell growth: The WarburQ effect.
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DOI：
10.1371/journal.pcbi.1005758
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发表时间：
2017-09
影响因子：
4.3
通讯作者：
Alberghina L
中科院分区：
文献类型：
--
作者：
Damiani C;Colombo R;Gaglio D;Mastroianni F;Pescini D;Westerhoff HV;Mauri G;Vanoni M;Alberghina L
癌细胞共有几种代谢特征，包括从葡萄糖有氧产生乳酸（瓦尔堡效应）、广泛的谷氨酰胺利用和受损的线粒体电子流。目前还不清楚这些代谢重排，可能涉及不同细胞中的不同分子事件，如何有助于癌细胞增殖的选择性优势。为了确定哪些代谢途径用于将葡萄糖和谷氨酰胺转化为平衡的能量和生物质生产，我们对人类中枢代谢模型进行了系统的基于约束的模拟。可行的通量空间的采样使我们能够获得大量的随机突变的细胞模拟在不同的谷氨酰胺和葡萄糖摄取速率。我们观察到，在有限的增殖细胞亚群中，大多数显示在氧气存在下葡萄糖发酵成乳酸。在谷氨酰胺的高利用率，葡萄糖的氧化利用减少，而从谷氨酰胺的乳酸的生产增加。只有当可用碳超过可用氧可以完全氧化的量时，才会观察到这种新出现的表型。在后一种条件下，标准通量平衡分析表明：这种代谢模式是最佳的，以最大限度地提高生物量和ATP的生产;它需要一个分支的TCA循环的活性，其中谷氨酰胺依赖性还原羧化合作生产的脂质和蛋白质;它是由各种氧化还原控制的代谢反应。在K-ras转化的细胞系中，我们实验性地评估谷氨酰胺诱导的代谢变化。我们通过扩展通量平衡分析来验证计算结果，该分析允许预测代谢物变化。总之，这些发现为癌细胞生长的代谢重编程逻辑提供了新的理解。已经确定了描述癌症发生、维持和进展中常见关键事件的特征。其中一个标志涉及维持增强的细胞增殖所需的代谢反应的重新布线。癌症标志的分子机制模型的可用性将极大地改善优化的个人治疗和新药发现。代谢是唯一的标志，它是目前可能得到大规模的数学模型，具有预测能力。在本文中，我们利用一个基于约束的模型的核心代谢所需的生物量转化的最相关的营养素-葡萄糖和谷氨酰胺-澄清控制癌症代谢的逻辑。我们最新报道，当可用的氧气不足以完全氧化可用的葡萄糖和谷氨酰胺碳的情况下观察到的正常氧气条件下，在人类和癌细胞生长在体外利用谷氨酰胺还原羧化和葡萄糖和谷氨酰胺转化为乳酸赋予生物质生产的优势。氧化还原稳态可以通过使用不同的替代途径来维持。总之，本文提供了一个逻辑解释之间的联系，代谢重新布线和增强的增殖，这可能会提供新的途径，靶向药物的发现和利用。
Cancer cells share several metabolic traits, including aerobic production of lactate from glucose (Warburg effect), extensive glutamine utilization and impaired mitochondrial electron flow. It is still unclear how these metabolic rearrangements, which may involve different molecular events in different cells, contribute to a selective advantage for cancer cell proliferation. To ascertain which metabolic pathways are used to convert glucose and glutamine to balanced energy and biomass production, we performed systematic constraint-based simulations of a model of human central metabolism. Sampling of the feasible flux space allowed us to obtain a large number of randomly mutated cells simulated at different glutamine and glucose uptake rates. We observed that, in the limited subset of proliferating cells, most displayed fermentation of glucose to lactate in the presence of oxygen. At high utilization rates of glutamine, oxidative utilization of glucose was decreased, while the production of lactate from glutamine was enhanced. This emergent phenotype was observed only when the available carbon exceeded the amount that could be fully oxidized by the available oxygen. Under the latter conditions, standard Flux Balance Analysis indicated that: this metabolic pattern is optimal to maximize biomass and ATP production; it requires the activity of a branched TCA cycle, in which glutamine-dependent reductive carboxylation cooperates to the production of lipids and proteins; it is sustained by a variety of redox-controlled metabolic reactions. In a K-ras transformed cell line we experimentally assessed glutamine-induced metabolic changes. We validated computational results through an extension of Flux Balance Analysis that allows prediction of metabolite variations. Taken together these findings offer new understanding of the logic of the metabolic reprogramming that underlies cancer cell growth. Hallmarks describing common key events in initiation, maintenance and progression of cancer have been identified. One hallmark deals with rewiring of metabolic reactions required to sustain enhanced cell proliferation. The availability of molecular, mechanistic models of cancer hallmarks will mightily improve optimized personal treatment and new drug discovery. Metabolism is the only hallmark for which it is currently possible to derive large scale mathematical models, which have predictive ability. In this paper, we exploit a constraint-based model of the core metabolism required for biomass conversion of the most relevant nutrients—glucose and glutamine—to clarify the logic of control of cancer metabolism. We newly report that, when available oxygen is not sufficient to fully oxidize available glucose and glutamine carbons–a situation compatible with that observed under normal oxygen conditions in human and in cancer cells growing in vitro—utilization of glutamine by reductive carboxylation and conversion of glucose and glutamine to lactate confer advantage for biomass production. Redox homeostasis can be maintained through the use of different alternative pathways. In conclusion, this paper offers a logic interpretation to the link between metabolic rewiring and enhanced proliferation, which may offer new approaches to targeted drug discovery and utilization.
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