定量分析丝氨酸/甘氨酸转换影响胃癌细胞增殖的动力学机制

The Quantitative Analysis of Dynamic Mechanisms Impacting Gastric Cancer Cell Proliferation via Serine/glycine Conversion

目的胃癌(GC)严重影响人类的健康生活,研究表明其与丝氨酸/甘氨酸代谢密切相关。丝氨酸/甘氨酸代谢对于肿瘤细胞的增殖能力具有重要影响。本文的研究目的是探究丝氨酸/甘氨酸代谢能够影响胃癌细胞增殖能力的分子机制。方法本文通过一种基于随机和非梯度系统的势能景观所建立的大型代谢网络动力学建模方法,构建了一个稳定的胃癌细胞代谢动力学模型。基于对模型的调控,定量分析丝氨酸/甘氨酸代谢影响胃癌细胞增殖的动力学机制。对一般代谢网络动力学方程添加随机噪声,通过随机动力学分解得到代谢网络参数空间的李雅普诺夫(Lyapunov)函数。进一步减少与随机波动相关的Lyapunov函数变化,从而得到稳定的代谢网络。结果在动力学参数不足的情况下,成功构建了胃癌细胞代谢网络的动力学模型。当胞外丝氨酸可用时,模型优先消耗丝氨酸;当甘氨酸生成丝氨酸的速率增加时,模型显著上调生成S-腺苷甲硫氨酸(SAM)和S-腺苷同型半胱氨酸(SAH)的稳态通量。结论本文证明了胃癌细胞对于丝氨酸的优先摄取以及丝氨酸/甘氨酸转化速率对SAM生成的重要作用,其可能通过调节细胞甲基化进程影响胃癌细胞的增殖能力,为靶向丝氨酸/甘氨酸代谢的癌症治疗提供了新的思路和方向。

Objective Gastric cancer(GC)seriously affects human health and life,and research has shown that it is closely related to the serine/glycine metabolism.The proliferation ability of tumor cells is greatly influenced by the metabolism of serine and glycine.The aim of this study was to investigate the molecular mechanism of serine/glycine metabolism can affect the proliferation of gastric cancer cells.Methods In this work,a stable metabolic dynamic model of gastric cancer cells was established via a large-scale metabolic network dynamic modeling method in terms of a potential landscape description of stochastic and non-gradient systems.Based on the regulation of the model,a quantitative analysis was conducted to investigate the dynamic mechanism of serine/glycine metabolism affecting the proliferation of gastric cancer cells.We introduced random noise to the kinetic equations of the general metabolic network,and applied stochastic kinetic decomposition to obtain the Lyapunov function of the metabolic network parameter space.A stable metabolic network was achieved by further reducing the change in the Lyapunov function tied to the stochastic fluctuations.Results Despite the unavailability of a large number of dynamic parameters,we were able to successfully construct a dynamic model for the metabolic network in gastric cancer cells.When extracellular serine is available,the model preferentially consumes serine.In addition,when the conversion rate of glycine to serine increases,the model significantly upregulates the steadystate fluxes of S-adenosylmethionine(SAM)and S-adenosyl homocysteine(SAH).Conclusion In this paper,we provide evidence supporting the preferential uptake of serine by gastric cancer cells and the important role of serine/glycine conversion rate in SAM generation,which may affect the proliferation ability of gastric cancer cells by regulating the cellular methylation process.This provides a new idea and direction for targeted cancer therapy based on serine/glycine metabolism.