Romo-González Marta, Ijurko Carla, Alonso María Teresa, Gómez de Cedrón Marta, Ramirez de Molina Ana, Soriano María Eugenia, Hernández-Hernández Ángel
Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, Salamanca, 37007, Spain; IBSAL (Instituto de Investigación Biomédica de Salamanca), Salamanca, 37007, Spain.
Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid and Consejo Superior de Investigaciones Científicas (CSIC), Valladolid, 47003, Spain.
Free Radic Biol Med. 2023 Mar;198:92-108. doi: 10.1016/j.freeradbiomed.2023.02.005. Epub 2023 Feb 9.
Cancer cells are characterised by an elevated metabolic plasticity and enhanced production of reactive oxygen species (ROS), two features acknowledged as hallmarks in cancer, with a high translational potential to the therapeutic setting. These aspects, that have been traditionally studied separately, are in fact intimately intermingled. As part of their transforming activity, some oncogenes stimulate rewiring of metabolic processes, whilst simultaneously promoting increased production of intracellular ROS. In this scenario the latest discoveries suggest the relevance of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOX) to connect ROS production and metabolic control. Here we have analysed the relevance of NOX2 and NOX4 in the regulation of metabolism in chronic myeloid leukaemia (CML), a neoplasia driven by the expression of the breakpoint cluster region-Abelson fusion oncogene (BCR-ABL). Silencing of NOX2 enhances glycolysis and oxidative phosphorylation rates, together with an enhanced production of mitochondrial ROS and a decrease in mitochondrial DNA copy number, which reflects mitochondrial dysfunction. NOX4 expression was upregulated upon NOX2 silencing, and this was required to alter mitochondrial function. Our results support the relevance of NOX2 to regulate metabolism-related signalling pathways downstream of BCR-ABL. Overall we show that NOX2, through the regulation of NOX4 expression, controls metabolism and mitochondrial function in CML cells. This notion was confirmed by transcriptomic analyses, that strongly relate both NOX isoforms with metabolism regulation in CML.
癌细胞的特征是代谢可塑性增强和活性氧（ROS）生成增加，这两个特征被认为是癌症的标志，在治疗方面具有很高的转化潜力。这些传统上分开研究的方面实际上紧密相连。作为其转化活性的一部分，一些癌基因刺激代谢过程的重新布线，同时促进细胞内ROS生成增加。在这种情况下，最新发现表明烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶（NOX）与连接ROS生成和代谢控制的相关性。在这里，我们分析了NOX2和NOX4在慢性粒细胞白血病（CML）代谢调节中的相关性，CML是一种由断裂点簇集区-阿贝尔森融合癌基因（BCR-ABL）表达驱动的肿瘤。沉默NOX2可提高糖酵解和氧化磷酸化速率，同时增强线粒体ROS生成并降低线粒体DNA拷贝数，这反映了线粒体功能障碍。NOX2沉默后NOX4表达上调，这是改变线粒体功能所必需的。我们的结果支持NOX2在调节BCR-ABL下游代谢相关信号通路中的相关性。总体而言，我们表明NOX2通过调节NOX4表达来控制CML细胞的代谢和线粒体功能。转录组分析证实了这一观点，该分析强烈将两种NOX同工型与CML中的代谢调节联系起来。
