Oncogene-induced metabolic reprograming supports cell growth and proliferation. Yet, it also links cancer cell survival to certain metabolic pathways and nutrients. In order to synthesise amino acids and nucleotides de novo for growth and proliferation, cancer cells depend on glycolysis, the cytoplasmic oxidation of glucose, which generates necessary metabolic intermediates and ATP. During glycolysis, NAD+ is used as the oxidizing agent and is thereby reduced into NADH. To ensure high glycolysis rates and maintain NADH/NAD+ homeostasis, cytoplasmic NAD+ has to be regenerated. The mitochondria are the major sites of NADH reoxidation into NAD+ where NADH-derived electrons enter the electron transport chain for ATP production. Since NADH/NAD+ cannot cross membranes, the malate-aspartate shuttle (MAS) or the glycerol-3-phosphate shuttle (GPS) are used as intermediate electron carriers. In addition, cytoplasmic NAD+ is generated by NADH-electron transfer to pyruvate, reducing it to lactate (the Warburg effect). NADH/NAD+ homeostasis plays a pivotal role in cancer cell survival, but our knowledge about the involved regulatory mechanisms is still limited. Here, we show that the proto-oncogenic transcription factor C/EBPβ-LIP stimulates both glycolysis and the MAS. Inhibition of glycolysis with ongoing C/EBPβ-LIP-induced MAS activity results in NADH depletion and apoptosis that can be rescued by inhibiting either the MAS or other NADH-consuming processes. Therefore, beyond the discovery of C/EBPβ-LIP as a dual activator of glycolysis and the MAS, this study indicates that simultaneous inhibition of glycolysis and lowering of the NADH/NAD+ ratio may be considered to treat cancer.

中文翻译：

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C /EBPβ-LIP双重激活糖酵解和苹果酸天冬氨酸穿梭，以维持NADH / NAD +稳态

癌基因诱导的代谢重编程支持细胞生长和增殖。然而，它也将癌细胞的存活与某些代谢途径和营养物质联系起来。为了从头合成用于生长和增殖的氨基酸和核苷酸，癌细胞依赖于糖酵解，即葡萄糖的细胞质氧化，产生必要的代谢中间体和ATP。在糖酵解过程中，NAD +用作氧化剂，因此被还原为NADH。为了确保高糖酵解速率并维持NADH / NAD +稳态，必须再生细胞质NAD +。线粒体是NADH再氧化成NAD +的主要位点，其中NADH衍生的电子进入电子传输链以产生ATP。由于NADH / NAD +无法穿过膜，苹果酸-天冬氨酸穿梭（MAS）或甘油3-磷酸穿梭（GPS）用作中间电子载体。此外，细胞质NAD +是通过将NADH电子转移至丙酮酸而生成的，从而使其还原为乳酸（沃堡效应）。NADH / NAD +动态平衡在癌细胞存活中起着关键作用，但是我们对相关调控机制的了解仍然有限。在这里，我们表明原致癌转录因子C /EBPβ-LIP刺激糖酵解和MAS。持续的C /EBPβ-LIP诱导的MAS活性抑制糖酵解会导致NADH耗竭和凋亡，这可以通过抑制MAS或其他消耗NADH的过程来挽救。因此，除了发现C /EBPβ-LIP作为糖酵解和MAS的双重激活剂外，