Division of Hematology/ Oncology, Department of Medicine, James Graham Brown Cancer Center, University of Louisville, Kentucky 40202, USA.
Curr Pharm Biotechnol. 2013;14(3):251-60. doi: 10.2174/1389201011314030002.
High glucose uptake is a characteristic of most metastatic tumors and activation of Ras signaling in immortalized cells increases glycolytic flux into lactate, de novo nucleic acid synthesis and the tricarboxylic acid cycle, and increases NADH shuttling, oxygen consumption and uncoupling of ATP synthase from the proton gradient. Fructose-2,6- bisphosphate, C-Myc, HIF1α and AKT each have been found to be key regulators of glycolysis and to be controlled by Ras signaling, and there is abundant evidence for cross-talk between these regulators. The reprogramming of glycolytic and mitochondrial metabolism by Ras enables an integrated activation of energetic and anabolic pathways via the redox state of NADH that is required for the survival and growth of neoplastic cells in poorly vascularized tumors. Several small molecule antagonists specific for essential metabolic enzymes have been found to be selectively toxic to Ras-transformed cells as opposed to wild-type cells, indicating that this metabolic reprogramming and addiction may have utility for the development of anti-neoplastic agents.
高葡萄糖摄取是大多数转移性肿瘤的特征，而 Ras 信号通路在永生化细胞中的激活会增加糖酵解通量转化为乳酸、从头合成核酸以及三羧酸循环，并增加 NADH 穿梭、耗氧量以及 ATP 合酶与质子梯度的解耦。已经发现果糖-2,6-二磷酸、C-Myc、HIF1α 和 AKT 都是糖酵解的关键调节因子，并受到 Ras 信号通路的调控，而且这些调节因子之间存在大量的交叉对话证据。Ras 使糖酵解和线粒体代谢重新编程，通过 NADH 的氧化还原状态，使能量和合成代谢途径得到综合激活，这是在血管生成不良的肿瘤中肿瘤细胞存活和生长所必需的。已经发现，几种针对必需代谢酶的小分子拮抗剂对 Ras 转化细胞具有选择性毒性，而对野生型细胞没有毒性，这表明这种代谢重编程和成瘾可能对开发抗肿瘤药物具有实用价值。
