探索星形胶质细胞和胶质母细胞瘤代谢行为的差异:通量平衡分析方法。

Systems and Synthetic Biology Pub Date : 2015-12-01 Epub Date: 2015-10-13 DOI:10.1007/s11693-015-9183-9
Rupa Bhowmick, Abhishek Subramanian, Ram Rup Sarkar
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引用次数: 8

摘要

脑癌表现出复杂的代谢行为,以适应外部缺氧环境和活性氧产生的内部应激。为了在这些苛刻的条件下生存,胶质母细胞瘤细胞与其前身星形胶质细胞相比,发展出一种拮抗代谢表型,从而消耗了预期用于滋养神经元的资源。胶质母细胞瘤大规模代谢功能的复杂性和累积效应大多未被探索。在这项研究中,我们重建了一个代谢网络,包括与星形胶质细胞相比,胶质母细胞瘤细胞中已知的不受调节的途径。该网络由147个编码酶的基因组成,分布在五个不同的模型室中,执行247个反应,然后使用基于约束的建模方法通过重建星形胶质细胞和胶质母细胞瘤的场景进行研究,并使用现有的实验证据进行验证。根据我们的分析,我们预测星形胶质细胞对甘氨酸的需求主要由内部甘氨酸-丝氨酸代谢来满足,而胶质母细胞瘤细胞需要外部摄取甘氨酸来利用它来生产谷胱甘肽。此外,胱氨酸和葡萄糖被确定为胶质母细胞瘤生长的主要贡献者。我们还提出了一套广泛的单致死和双致死反应敲除,进一步扰动以确定它们作为可能的化疗靶点的作用。这些模拟结果表明,除靶向中枢碳代谢反应外,敲除属于甘氨酸-丝氨酸代谢的反应可以有效地抑制胶质母细胞瘤的生长。联合靶向甘氨酸转运蛋白与任何其他属于甘氨酸-丝氨酸代谢的反应证明对胶质母细胞瘤的生长是致命的。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Exploring the differences in metabolic behavior of astrocyte and glioblastoma: a flux balance analysis approach.

Exploring the differences in metabolic behavior of astrocyte and glioblastoma: a flux balance analysis approach.

Exploring the differences in metabolic behavior of astrocyte and glioblastoma: a flux balance analysis approach.

Exploring the differences in metabolic behavior of astrocyte and glioblastoma: a flux balance analysis approach.

Brain cancers demonstrate a complex metabolic behavior so as to adapt the external hypoxic environment and internal stress generated by reactive oxygen species. To survive in these stringent conditions, glioblastoma cells develop an antagonistic metabolic phenotype as compared to their predecessors, the astrocytes, thereby quenching the resources expected for nourishing the neurons. The complexity and cumulative effect of the large scale metabolic functioning of glioblastoma is mostly unexplored. In this study, we reconstruct a metabolic network comprising of pathways that are known to be deregulated in glioblastoma cells as compared to the astrocytes. The network, consisted of 147 genes encoding for enzymes performing 247 reactions distributed across five distinct model compartments, was then studied using constrained-based modeling approach by recreating the scenarios for astrocytes and glioblastoma, and validated with available experimental evidences. From our analysis, we predict that glycine requirement of the astrocytes are mostly fulfilled by the internal glycine-serine metabolism, whereas glioblastoma cells demand an external uptake of glycine to utilize it for glutathione production. Also, cystine and glucose were identified to be the major contributors to glioblastoma growth. We also proposed an extensive set of single and double lethal reaction knockouts, which were further perturbed to ascertain their role as probable chemotherapeutic targets. These simulation results suggested that, apart from targeting the reactions of central carbon metabolism, knockout of reactions belonging to the glycine-serine metabolism effectively reduce glioblastoma growth. The combinatorial targeting of glycine transporter with any other reaction belonging to glycine-serine metabolism proved lethal to glioblastoma growth.

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