Cancer Sciences Unit, Faculty of Medicine, University of Southampton, SO16 6YD England, UK.
Institute for Life Sciences, University of Southampton, SO17 1BJ England, UK.
Sci Signal. 2020 May 5;13(630):eaau9529. doi: 10.1126/scisignal.aau9529.
High rates of glycolysis in cancer cells are a well-established characteristic of many human tumors, providing rapidly proliferating cancer cells with metabolites that can be used as precursors for anabolic pathways. Maintenance of high glycolytic rates depends on the lactate dehydrogenase-catalyzed regeneration of NAD from GAPDH-generated NADH because an increased NADH:NAD ratio inhibits GAPDH. Here, using human breast cancer cell models, we identified a pathway in which changes in the extramitochondrial-free NADH:NAD ratio signaled through the CtBP family of NADH-sensitive transcriptional regulators to control the abundance and activity of p53. NADH-free forms of CtBPs cooperated with the p53-binding partner HDM2 to suppress p53 function, and loss of these forms in highly glycolytic cells resulted in p53 accumulation. We propose that this pathway represents a "glycolytic stress response" in which the initiation of a protective p53 response by an increased NADH:NAD ratio enables cells to avoid cellular damage caused by mismatches between metabolic supply and demand.
癌细胞中糖酵解的高速率是许多人类肿瘤的一个既定特征，为快速增殖的癌细胞提供可作为合成代谢途径前体的代谢物。维持高糖酵解速率取决于乳酸脱氢酶催化的 NAD 从 GAPDH 产生的 NADH 中的再生，因为增加的 NADH:NAD 比抑制 GAPDH。在这里，我们使用人类乳腺癌细胞模型，鉴定了一条途径，其中细胞外游离 NADH:NAD 比的变化通过 CtBP 家族的 NADH 敏感转录调节剂发出信号，以控制 p53 的丰度和活性。CtBP 的 NADH 游离形式与 p53 结合伙伴 HDM2 合作抑制 p53 功能，而在高度糖酵解的细胞中这些形式的丢失导致 p53 积累。我们提出，该途径代表了一种“糖酵解应激反应”，其中增加的 NADH:NAD 比引发保护性 p53 反应，使细胞能够避免代谢供应和需求之间不匹配造成的细胞损伤。
