Van Hée Vincent F, Pérez-Escuredo Jhudit, Cacace Andrea, Copetti Tamara, Sonveaux Pierre
Pole of Pharmacology, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain (UCL) Medical School Brussels, Belgium.
Front Pharmacol. 2015 Oct 13;6:228. doi: 10.3389/fphar.2015.00228. eCollection 2015.
The lactate anion is currently emerging as an oncometabolite. Lactate, produced and exported by glycolytic and glutaminolytic cells in tumors, can be recycled as an oxidative fuel by oxidative tumors cells. Independently of hypoxia, it can also activate transcription factor hypoxia-inducible factor-1 (HIF-1) in tumor and endothelial cells, promoting angiogenesis. These protumoral activities of lactate depend on lactate uptake, a process primarily facilitated by the inward, passive lactate-proton symporter monocarboxylate transporter 1 (MCT1); the conversion of lactate and NAD(+) to pyruvate, NADH and H(+) by lactate dehydrogenase-1 (LDH-1); and a competition between pyruvate and α-ketoglutarate that inhibits prolylhydroxylases (PHDs). Endothelial cells do not primarily use lactate as an oxidative fuel but, rather, as a signaling agent. In addition to HIF-1, lactate can indeed activate transcription factor nuclear factor-κB (NF-κB) in these cells, through a mechanism not only depending on PHD inhibition but also on NADH alimenting NAD(P)H oxidases to generate reactive oxygen species (ROS). While NF-κB activity in endothelial cells promotes angiogenesis, NF-κB activation in tumor cells is known to stimulate tumor progression by conferring resistance to apoptosis, stemness, pro-angiogenic and metastatic capabilities. In this study, we therefore tested whether exogenous lactate could activate NF-κB in oxidative tumor cells equipped for lactate signaling. We report that, precisely because they are oxidative, HeLa and SiHa human tumor cells do not activate NF-κB in response to lactate. Indeed, while lactate-derived pyruvate is well-known to inhibit PHDs in these cells, we found that NADH aliments oxidative phosphorylation (OXPHOS) in mitochondria rather than NAD(P)H oxidases in the cytosol. These data were confirmed using oxidative human Cal27 and MCF7 tumor cells. This new information positions the malate-aspartate shuttle as a key player in the oxidative metabolism of lactate: similar to glycolysis that aliments OXPHOS with pyruvate produced by pyruvate kinase and NADH produced by glyceraldehyde-3-phosphate dehydrogenase (GAPDH), oxidative lactate metabolism aliments OXPHOS in oxidative tumor cells with pyruvate and NADH produced by LDH1.
乳酸阴离子目前正作为一种肿瘤代谢物崭露头角。肿瘤中通过糖酵解和谷氨酰胺分解产生并输出的乳酸，可被氧化型肿瘤细胞作为氧化燃料再利用。与缺氧无关，它还能激活肿瘤细胞和内皮细胞中的转录因子缺氧诱导因子-1（HIF-1），促进血管生成。乳酸的这些促肿瘤活性依赖于乳酸摄取，这一过程主要由内向型、被动的乳酸-质子同向转运体单羧酸转运蛋白1（MCT1）推动；乳酸脱氢酶-1（LDH-1）将乳酸和NAD(+)转化为丙酮酸、NADH和H(+)；以及丙酮酸和α-酮戊二酸之间的竞争抑制脯氨酰羟化酶（PHD）。内皮细胞并非主要将乳酸用作氧化燃料，而是用作信号分子。除了HIF-1，乳酸确实能在这些细胞中激活转录因子核因子-κB（NF-κB），其机制不仅依赖于PHD抑制，还依赖于NADH为NAD(P)H氧化酶提供原料以产生活性氧（ROS）。虽然内皮细胞中的NF-κB活性促进血管生成，但已知肿瘤细胞中的NF-κB激活通过赋予抗凋亡、干性、促血管生成和转移能力来刺激肿瘤进展。因此，在本研究中，我们测试了外源性乳酸是否能在具备乳酸信号传导能力的氧化型肿瘤细胞中激活NF-κB。我们报告称，恰恰因为HeLa和SiHa人肿瘤细胞是氧化型的，它们不会因乳酸而激活NF-κB。事实上，虽然乳酸衍生的丙酮酸在这些细胞中众所周知会抑制PHD，但我们发现NADH为线粒体中的氧化磷酸化（OXPHOS）提供原料，而非为胞质溶胶中的NAD(P)H氧化酶提供原料。使用氧化型人Cal27和MCF7肿瘤细胞证实了这些数据。这一新信息将苹果酸-天冬氨酸穿梭定位为乳酸氧化代谢中的关键参与者：类似于糖酵解为OXPHOS提供丙酮酸激酶产生的丙酮酸和甘油醛-3-磷酸脱氢酶（GAPDH）产生的NADH，氧化型乳酸代谢为氧化型肿瘤细胞中的OXPHOS提供LDH1产生的丙酮酸和NADH。
