文章：

解析淋巴瘤中瓦伯格悖论的代谢基础与分子调控网络

Deciphering the Metabolic Basis and Molecular Circuitry of the Warburg Paradox in Lymphoma

原文发布日期：25 October 2024

DOI: 10.3390/cancers16213606

类型: Article

开放获取: 是

英文摘要：

Background/Objectives: Warburg’s metabolic paradox illustrates that malignant cells require both glucose and oxygen to survive, even after converting glucose into lactate. It remains unclear whether sparing glucose from oxidation intersects with TCA cycle continuity and if this confers any metabolic advantage in proliferating cancers. This study seeks to understand the mechanistic basis of Warburg’s paradox and its overall implications for lymphomagenesis.Methods: Using metabolomics, we first examined the metabolomic profiles, glucose, and glutamine carbon labeling patterns in the metabolism during the cell cycle. We then investigated proliferation-specific metabolic features of malignant and nonmalignant cells. Finally, through bioinformatics and the identification of appropriate pharmacological targets, we established malignant-specific proliferative implications for the Warburg paradox associated with metabolic features in this study.Results: Our results indicate that pyruvate, lactate, and alanine levels surge during the S phase and are correlated with nucleotide synthesis. By using13C1,2-Glucose and13C6,15N2-Glutamine isotope tracers, we observed that the transamination of pyruvate to alanine is elevated in lymphoma and coincides with the entry of glutamine carbon into the TCA cycle. Finally, by using fludarabine as a strong inhibitor of lymphoma, we demonstrate that disrupting the transamination of pyruvate to alanine correlates with the simultaneous suppression of glucose-derived nucleotide biosynthesis and glutamine carbon entry into the TCA cycle.Conclusions: We conclude that the transamination of pyruvate to alanine intersects with reduced glucose oxidation and maintains the TCA cycle as a critical metabolic feature of Warburg’s paradox and lymphomagenesis.

摘要翻译： 

背景/目的：瓦博格代谢悖论指出，恶性细胞即使在将葡萄糖转化为乳酸后，仍需要葡萄糖和氧气才能存活。目前尚不清楚葡萄糖氧化节约是否与三羧酸循环的连续性相交，以及这是否为增殖性癌症带来任何代谢优势。本研究旨在探讨瓦博格悖论的机制基础及其对淋巴瘤发生的整体影响。方法：通过代谢组学分析，我们首先检测了细胞周期中代谢的代谢组学特征、葡萄糖和谷氨酰胺碳标记模式。随后，我们研究了恶性和非恶性细胞中增殖特异性代谢特征。最后，通过生物信息学分析和适当的药理学靶点鉴定，我们建立了与本研究代谢特征相关的瓦博格悖论对恶性特异性增殖的影响。结果：我们的结果表明，丙酮酸、乳酸和丙氨酸水平在S期急剧上升，并与核苷酸合成相关。通过使用13C1,2-葡萄糖和13C6,15N2-谷氨酰胺同位素示踪剂，我们观察到淋巴瘤中丙酮酸向丙氨酸的转氨作用增强，并与谷氨酰胺碳进入三羧酸循环同时发生。最后，通过使用氟达拉滨作为淋巴瘤的强效抑制剂，我们证明破坏丙酮酸向丙氨酸的转氨作用与同时抑制葡萄糖来源的核苷酸生物合成和谷氨酰胺碳进入三羧酸循环相关。结论：我们得出结论，丙酮酸向丙氨酸的转氨作用与葡萄糖氧化减少相交，并维持三羧酸循环作为瓦博格悖论和淋巴瘤发生的关键代谢特征。

原文链接：

Deciphering the Metabolic Basis and Molecular Circuitry of the Warburg Paradox in Lymphoma