High extracellular lactate causes reductive carboxylation in breast tissue cell lines grown under normoxic conditions
| Autor: | Sarah W. Harcum, Daniel C. Odenwelder, Arthur Nathan Brodsky |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Composite Particles Glutamine Cell Culture Techniques 02 engineering and technology Biochemistry Glucose Metabolism Isotopes Glycolysis Amino Acids Carbon Isotopes Multidisciplinary Chemistry Organic Compounds Physics Acidic Amino Acids Monosaccharides Ketones Physical Sciences Medicine Carbohydrate Metabolism Metabolic Labeling Energy source Oxidation-Reduction Intracellular Research Article Pyruvate Cell Physiology Atoms Science 0206 medical engineering Citric Acid Cycle Carbohydrates Breast Neoplasms Research and Analysis Methods Citric Acid 03 medical and health sciences Cell Line Tumor Extracellular Humans Lactic Acid Molecular Biology Techniques Particle Physics Molecular Biology Organic Chemistry Chemical Compounds Biology and Life Sciences Proteins Metabolism Cell Biology Metabolic Flux Analysis Cell Metabolism Citric acid cycle Amino Acid Metabolism 030104 developmental biology Glucose Cell culture Cell Labeling Cancer cell Acids 020602 bioinformatics |
| Zdroj: | PLoS ONE PLoS ONE, Vol 14, Iss 6, p e0213419 (2019) |
| ISSN: | 1932-6203 |
| Popis: | In cancer tumors, lactate accumulation was initially attributed to high glucose consumption associated with the Warburg Effect. Now it is evident that lactate can also serve as an energy source in cancer cell metabolism. Additionally, lactate has been shown to promote metastasis, generate gene expression patterns in cancer cells consistent with "cancer stem cell" phenotypes, and result in treatment resistant tumors. Therefore, the goal of this work was to quantify the impact of lactate on metabolism in three breast cell lines (one normal and two breast cancer cell lines-MCF 10A, MCF7, and MDA-MB-231), in order to better understand the role lactate may have in different disease cell types. Parallel labeling metabolic flux analysis (13C-MFA) was used to quantify the intracellular fluxes under normal and high extracellular lactate culture conditions. Additionally, high extracellular lactate cultures were labelled in parallel with [U-13C] lactate, which provided qualitative information regarding the lactate uptake and metabolism. The 13C-MFA model, which incorporated the measured extracellular fluxes and the parallel labeling mass isotopomer distributions (MIDs) for five glycolysis, four tricarboxylic acid cycle (TCA), and three intracellular amino acid metabolites, predicted lower glycolysis fluxes in the high lactate cultures. All three cell lines experienced reductive carboxylation of glutamine to citrate in the TCA cycle as a result of high extracellular lactate. Reductive carboxylation previously has been observed under hypoxia and other mitochondrial stresses, whereas these cultures were grown aerobically. In addition, this is the first study to investigate the intracellular metabolic responses of different stages of breast cancer progression to high lactate exposure. These results provide insight into the role lactate accumulation has on metabolic reaction distributions in the different disease cell types while the cells are still proliferating in lactate concentrations that do not significantly decrease exponential growth rates. |
| Databáze: | OpenAIRE |
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