Acidosis induces reprogramming of cellular metabolism to mitigate oxidative stress
Acidosis induces reprogramming of cellular metabolism to mitigate oxidative stress
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DOI：
10.1186/2049-3002-1-23
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发表时间：
2013-12-01
影响因子：
5.9
通讯作者：
Chi, Jen-Tsan
中科院分区：
文献类型：
--
作者：
LaMonte, Gregory;Tang, Xiaohu;Chi, Jen-Tsan
背景：多种致癌和环境因素改变肿瘤代谢，以满足肿瘤发生过程中不同的细胞生物合成和生物能量需求。细胞外酸中毒是实体瘤中常见的微环境应激，但对其代谢影响知之甚少，特别是在缺氧的情况下。为了表征肿瘤细胞对酸中毒代谢适应的程度，我们采用稳定同位素示踪剂来检查酸中毒如何影响暴露于细胞外酸中毒的乳腺癌细胞中的葡萄糖、谷氨酰胺和棕榈酸代谢。结果：酸中毒增加了谷氨酰胺分解和脂肪酸β-氧化，从而贡献代谢中间体来驱动三羧酸循环（TCA循环）和ATP生成。酸中毒还通过抑制 GCLC/GCLM 表达，导致谷氨酰胺分解和新型谷胱甘肽 (GSH) 合成脱钩。我们进一步发现，酸中毒会使葡萄糖从乳酸产生转向磷酸戊糖途径（PPP）的氧化分支。这些变化都有助于增加烟酰胺腺嘌呤二核苷酸磷酸 (NADPH) 的产生，并抵消酸中毒时活性氧 (ROS) 的增加。酸中毒时新型 GSH 合成的减少可能解释了回收现有 GSH 库时对 NADPH 的需求增加的原因。有趣的是，酸中毒还使新型核糖合成与氧化 PPP 断开，似乎将 PPP 代谢物重新路由至 TCA 循环。最后，我们发现酸中毒会激活 p53，这至少部分是通过诱导 G6PD 和 GLS2 基因来促进 PPP 的增强和谷氨酰胺分解的增加。结论：酸中毒改变了几种主要代谢物的细胞代谢，从而导致显着程度的代谢不灵活性。暴露于酸中毒的细胞在很大程度上依赖线粒体代谢来产生能量，以至于代谢中间体被重新引导远离其他几个关键的代谢过程，包括核糖和谷胱甘肽的合成。这些改变导致细胞增殖减少和对 ROS 的敏感性增加。总的来说，这些数据揭示了 p53 在酸中毒下细胞代谢重编程中的作用，以增加生物能能力和 ROS 中和。了解癌细胞在酸中毒下产生的代谢适应可能为产生更具肿瘤特异性的抗肿瘤治疗药物提供了机会。
Background: A variety of oncogenic and environmental factors alter tumor metabolism to serve the distinct cellular biosynthetic and bioenergetic needs present during oncogenesis. Extracellular acidosis is a common microenvironmental stress in solid tumors, but little is known about its metabolic influence, particularly when present in the absence of hypoxia. In order to characterize the extent of tumor cell metabolic adaptations to acidosis, we employed stable isotope tracers to examine how acidosis impacts glucose, glutamine, and palmitate metabolism in breast cancer cells exposed to extracellular acidosis.Results: Acidosis increased both glutaminolysis and fatty acid beta-oxidation, which contribute metabolic intermediates to drive the tricarboxylic acid cycle (TCA cycle) and ATP generation. Acidosis also led to a decoupling of glutaminolysis and novel glutathione (GSH) synthesis by repressing GCLC/GCLM expression. We further found that acidosis redirects glucose away from lactate production and towards the oxidative branch of the pentose phosphate pathway (PPP). These changes all serve to increase nicotinamide adenine dinucleotide phosphate (NADPH) production and counter the increase in reactive oxygen species (ROS) present under acidosis. The reduced novel GSH synthesis under acidosis may explain the increased demand for NADPH to recycle existing pools of GSH. Interestingly, acidosis also disconnected novel ribose synthesis from the oxidative PPP, seemingly to reroute PPP metabolites to the TCA cycle. Finally, we found that acidosis activates p53, which contributes to both the enhanced PPP and increased glutaminolysis, at least in part, through the induction of G6PD and GLS2 genes.Conclusions: Acidosis alters the cellular metabolism of several major metabolites, which induces a significant degree of metabolic inflexibility. Cells exposed to acidosis largely rely upon mitochondrial metabolism for energy generation to the extent that metabolic intermediates are redirected away from several other critical metabolic processes, including ribose and glutathione synthesis. These alterations lead to both a decrease in cellular proliferation and increased sensitivity to ROS. Collectively, these data reveal a role for p53 in cellular metabolic reprogramming under acidosis, in order to permit increased bioenergetic capacity and ROS neutralization. Understanding the metabolic adaptations that cancer cells make under acidosis may present opportunities to generate anti-tumor therapeutic agents that are more tumor-specific.