Dias Ana S, Almeida Catarina R, Helguero Luisa, Duarte Iola F
CICECO - Aveiro Institute of Materials, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal.
iBiMED - Institute of Biomedicine, Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal.
J Proteome Res. 2024 Dec 6;23(12):5498-5510. doi: 10.1021/acs.jproteome.4c00654. Epub 2024 Oct 30.
Pharmacological targeting of metabolic pathways represents an appealing strategy to selectively kill cancer cells while promoting antitumor functions of stromal cells. In this study, we assessed the effectiveness of 13 metabolic drugs (MDs) in steering generated breast tumor-educated macrophages (TEMs) toward an antitumoral phenotype. For that, the production of vascular endothelial growth factor (VEGF) and tumor necrosis factor α (TNF-α), two important regulators of tumor progression, was evaluated. Notably, dichloroacetate (DCA), 6-aminonicotinamide (6-AN), and etomoxir decreased VEGF production and enhanced TNF-α release. Hence, we further clarified their impact on TEM metabolism using an untargeted NMR-based metabolomics approach. DCA downregulated glycolysis and enhanced the utilization of extracellular substrates like lactate while reconfiguring lipid metabolism. Several DCA-induced changes significantly correlated with heightened TNF-α production in response to pro-inflammatory stimulation. The inhibition of the pentose phosphate pathway by 6-AN was accompanied by enhanced glutaminolysis, which correlated with a decreased level of VEGF production. In etomoxir-treated TEM, inhibition of fatty acid oxidation was compensated through upregulation of glycolysis, catabolism of intracellular amino acids, and consumption of extracellular branched chain alpha-ketoacids (BCKA) and citrate. Overall, our results offer a comprehensive view of the metabolic signature of each MD in breast TEM and highlight putative correlations with phenotypic effects.
对代谢途径进行药理学靶向是一种有吸引力的策略，可在促进基质细胞抗肿瘤功能的同时选择性杀死癌细胞。在本研究中，我们评估了13种代谢药物（MDs）在引导生成的乳腺癌相关巨噬细胞（TEMs）向抗肿瘤表型转变方面的有效性。为此，我们评估了肿瘤进展的两个重要调节因子血管内皮生长因子（VEGF）和肿瘤坏死因子α（TNF-α）的产生。值得注意的是，二氯乙酸（DCA）、6-氨基烟酰胺（6-AN）和依托莫昔降低了VEGF的产生并增强了TNF-α的释放。因此，我们使用基于非靶向核磁共振的代谢组学方法进一步阐明了它们对TEM代谢的影响。DCA下调糖酵解并增强了对细胞外底物（如乳酸）的利用，同时重新配置脂质代谢。DCA诱导的几种变化与促炎刺激后TNF-α产生的增加显著相关。6-AN对磷酸戊糖途径的抑制伴随着谷氨酰胺分解的增强，这与VEGF产生水平的降低相关。在依托莫昔处理的TEM中，脂肪酸氧化的抑制通过糖酵解的上调、细胞内氨基酸的分解代谢以及细胞外支链α-酮酸（BCKA）和柠檬酸盐的消耗得到补偿。总体而言，我们的结果全面展示了每种MD在乳腺TEM中的代谢特征，并突出了与表型效应的潜在相关性。
