da Veiga Moreira Jorgelindo, De Staercke Lenny, César Martínez-Basilio Pablo, Gauthier-Thibodeau Sandrine, Montégut Léa, Schwartz Laurent, Jolicoeur Mario
Research Laboratory in Applied Metabolic Engineering, Department of Chemical Engineering, École Polytechnique de Montréal, P.O. Box 6079, Centre-Ville Station, Montréal, QC H3C 3A7, Canada.
Assistance Publique des Hôpitaux de Paris, Avenue Victoria, 75003 Paris, France.
Metabolites. 2021 May 26;11(6):344. doi: 10.3390/metabo11060344.
Tumor cells are known to favor a glycolytic metabolism over oxidative phosphorylation (OxPhos), which takes place in mitochondria, to produce the energy and building blocks essential for cell maintenance and cell growth. This phenotypic property of tumor cells gives them several advantages over normal cells and is known as the Warburg effect. Tumors can be treated as a metabolic disease by targeting their bioenergetics capacity. Alpha-lipoic acid (ALA) and calcium hydroxycitrate (HCA) are two drugs known to target the Warburg effect in tumor cells and hence induce the mitochondria for ATP production. However, tumor cells, known to have an increased flux through glycolysis, are not able to handle the activation of their mitochondria by drugs or any other condition, leading to decoupling of gene regulation. In this study, these drug effects were studied by mimicking an inflammatory condition through the imposition of a hyperosmotic condition in Chinese hamster ovary (CHO) cells, which behave similarly to tumor cells. Indeed, CHO cells grown in high osmolarity conditions, using 200 mM mannitol, showed a pronounced Warburg effect phenotype. Our results show that hyperosmolar conditions triggered high-throughput glycolysis and enhanced glutaminolysis in CHO cells, such as during cancer cell proliferation in inflammatory tissue. Finally, we found that the hyperosmolar condition was correlated with increased mitochondrial membrane potential (ΔΨm) but mitochondrial horsepower seemed to vanish (h = Δp/ΔΨm), which may be explained by mitochondrial hyperfusion.
已知肿瘤细胞相较于在线粒体中发生的氧化磷酸化（OxPhos），更倾向于糖酵解代谢，以产生细胞维持和生长所必需的能量及构建模块。肿瘤细胞的这种表型特性使其相较于正常细胞具有若干优势，这一现象被称为瓦伯格效应。通过靶向肿瘤细胞的生物能量学能力，肿瘤可被视为一种代谢性疾病。α-硫辛酸（ALA）和羟基柠檬酸钙（HCA）是已知的两种靶向肿瘤细胞中瓦伯格效应从而诱导线粒体产生三磷酸腺苷（ATP）的药物。然而，已知糖酵解通量增加的肿瘤细胞无法应对药物或任何其他条件对其线粒体的激活，从而导致基因调控解偶联。在本研究中，通过在中国仓鼠卵巢（CHO）细胞中施加高渗条件来模拟炎症状态，研究这些药物的作用，CHO细胞的行为与肿瘤细胞相似。事实上，在使用200 mM甘露醇的高渗条件下生长的CHO细胞表现出明显的瓦伯格效应表型。我们的结果表明，高渗条件触发了CHO细胞中的高通量糖酵解并增强了谷氨酰胺分解代谢，就如同炎症组织中癌细胞增殖时的情况一样。最后，我们发现高渗条件与线粒体膜电位（ΔΨm）升高相关，但线粒体功率似乎消失了（h = Δp/ΔΨm），这可能是由线粒体过度融合所解释的。
