San-Millán Iñigo, Julian Colleen G, Matarazzo Christopher, Martinez Janel, Brooks George A
Department of Medicine, Division of Endocrinology, Metabolism and Diabetes, University of Colorado School of Medicine, Aurora, CO, United States.
Department of Human Physiology and Nutrition, University of Colorado, Colorado Springs, CO, United States.
Front Oncol. 2020 Jan 14;9:1536. doi: 10.3389/fonc.2019.01536. eCollection 2019.
Lactate is a ubiquitous molecule in cancer. In this exploratory study, our aim was to test the hypothesis that lactate could function as an oncometabolite by evaluating whether lactate exposure modifies the expression of oncogenes, or genes encoding transcription factors, cell division, and cell proliferation in MCF7 cells, a human breast cancer cell line. Gene transcription was compared between MCF7 cells incubated in (a) glucose/glutamine-free media (control), (b) glucose-containing media to stimulate endogenous lactate production (replicating some of the original Warburg studies), and (c) glucose-containing media supplemented with L-lactate (10 and 20 mM). We found that both endogenous, glucose-derived lactate and exogenous, lactate supplementation significantly affected the transcription of key oncogenes (MYC, RAS, and PI3KCA), transcription factors (HIF1A and E2F1), tumor suppressors (BRCA1, BRCA2) as well as cell cycle and proliferation genes involved in breast cancer (AKT1, ATM, CCND1, CDK4, CDKN1A, CDK2B) (0.001 < < 0.05 for all genes). Our findings support the hypothesis that lactate acts as an oncometabolite in MCF7 cells. Further research is necessary on other cell lines and biopsy cultures to show generality of the findings and reveal the mechanisms by which dysregulated lactate metabolism could act as an oncometabolite in carcinogenesis.
乳酸是癌症中普遍存在的一种分子。在这项探索性研究中，我们的目的是通过评估乳酸暴露是否会改变癌基因、编码转录因子、细胞分裂和细胞增殖相关基因在人乳腺癌细胞系MCF7细胞中的表达，来验证乳酸可作为一种癌代谢物的假说。我们比较了在以下三种条件下培养的MCF7细胞的基因转录情况：（a）无葡萄糖/谷氨酰胺培养基（对照）；（b）含葡萄糖培养基以刺激内源性乳酸生成（重复一些最初的瓦尔堡研究）；（c）添加L-乳酸（10 mM和20 mM）的含葡萄糖培养基。我们发现，内源性的葡萄糖衍生乳酸和外源性添加的乳酸均显著影响关键癌基因（MYC、RAS和PI3KCA）、转录因子（HIF1A和E2F1）、肿瘤抑制因子（BRCA1、BRCA2）以及参与乳腺癌的细胞周期和增殖相关基因（AKT1、ATM、CCND1、CDK4、CDKN1A、CDK2B）的转录（所有基因的P值均在0.001至0.05之间）。我们的研究结果支持了乳酸在MCF7细胞中作为癌代谢物的假说。有必要对其他细胞系和活检培养物进行进一步研究，以证实这些发现的普遍性，并揭示乳酸代谢失调在致癌过程中作为癌代谢物发挥作用的机制。
