文章：

米氏常数对癌细胞氧化还原平衡与乳酸分泌的重要性——重访瓦伯格效应

Importance of Michaelis Constants for Cancer Cell Redox Balance and Lactate Secretion—Revisiting the Warburg Effect

原文发布日期：21 June 2024

DOI: 10.3390/cancers16132290

类型: Article

开放获取: 是

英文摘要：

Cancer cells metabolize a large fraction of glucose to lactate, even under a sufficient oxygen supply. This phenomenon—the “Warburg Effect”—is often regarded as not yet understood. Cancer cells change gene expression to increase the uptake and utilization of glucose for biosynthesis pathways and glycolysis, but they do not adequately up-regulate the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS). Thereby, an increased glycolytic flux causes an increased production of cytosolic NADH. However, since the corresponding gene expression changes are not neatly fine-tuned in the cancer cells, cytosolic NAD+must often be regenerated by loading excess electrons onto pyruvate and secreting the resulting lactate, even under sufficient oxygen supply. Interestingly, the Michaelis constants (KMvalues) of the enzymes at the pyruvate junction are sufficient to explain the priorities for pyruvate utilization in cancer cells: 1. mitochondrial OXPHOS for efficient ATP production, 2. electrons that exceed OXPHOS capacity need to be disposed of and secreted as lactate, and 3. biosynthesis reactions for cancer cell growth. In other words, a number of cytosolic electrons need to take the “emergency exit” from the cell by lactate secretion to maintain the cytosolic redox balance.

摘要翻译： 

癌细胞即使在氧气供应充足的情况下，仍会将大量葡萄糖代谢为乳酸。这一现象——"瓦博格效应"——常被认为尚未被完全理解。癌细胞通过改变基因表达来增加葡萄糖的摄取和利用，以支持生物合成途径和糖酵解过程，但未能充分上调三羧酸循环和氧化磷酸化。因此，糖酵解通量的增加导致胞质中NADH产量上升。然而，由于癌细胞中相应的基因表达变化未能实现精准调控，即使在氧气充足条件下，胞质NADH通常仍需通过将过量电子转移至丙酮酸并分泌生成的乳酸来再生NAD+。值得注意的是，丙酮酸代谢节点相关酶的米氏常数足以解释癌细胞中丙酮酸利用的优先级：1. 通过线粒体氧化磷酸化高效产生ATP；2. 超出氧化磷酸化承载能力的过量电子需以乳酸形式排出；3. 支持癌细胞生长的生物合成反应。换言之，为维持胞质氧化还原平衡，大量胞质电子需通过乳酸分泌这一"应急通道"排出细胞。

原文链接：

Importance of Michaelis Constants for Cancer Cell Redox Balance and Lactate Secretion—Revisiting the Warburg Effect