Abstract:
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 (KM values) 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:
癌细胞将大部分葡萄糖代谢为乳酸,即使在充足的氧气供应下。这种现象-“Warburg效应”-通常被认为尚未被理解。癌细胞改变基因表达以增加生物合成途径和糖酵解的葡萄糖的摄取和利用。但它们不能充分上调三羧酸(TCA)循环和氧化磷酸化(OXPHOS)。因此,糖酵解通量的增加导致胞质NADH的产生增加。然而,由于癌细胞中相应的基因表达变化没有被巧妙地微调,胞质NAD+通常必须通过将过量电子加载到丙酮酸上并分泌产生的乳酸来再生,即使在充足的氧气供应下。有趣的是,丙酮酸接合处的酶的米氏常数(KM值)足以解释丙酮酸在癌细胞中利用的优先级:1.用于有效生产ATP的线粒体OXPHOS,2.超过OXPHOS容量的电子需要被处理并分泌为乳酸,and3.癌细胞生长的生物合成反应。换句话说,许多胞质电子需要通过乳酸分泌从细胞中“紧急出口”来维持胞质氧化还原平衡。