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High extracellular lactate causes reductive carboxylation in breast tissue cell lines grown under normoxic conditions

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 expre...

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Autores principales: Brodsky, Arthur Nathan, Odenwelder, Daniel C., Harcum, Sarah W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6557470/
https://www.ncbi.nlm.nih.gov/pubmed/31181081
http://dx.doi.org/10.1371/journal.pone.0213419
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author Brodsky, Arthur Nathan
Odenwelder, Daniel C.
Harcum, Sarah W.
author_facet Brodsky, Arthur Nathan
Odenwelder, Daniel C.
Harcum, Sarah W.
author_sort Brodsky, Arthur Nathan
collection PubMed
description 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 ((13)C-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-(13)C] lactate, which provided qualitative information regarding the lactate uptake and metabolism. The (13)C-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.
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spelling pubmed-65574702019-06-17 High extracellular lactate causes reductive carboxylation in breast tissue cell lines grown under normoxic conditions Brodsky, Arthur Nathan Odenwelder, Daniel C. Harcum, Sarah W. PLoS One Research Article 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 ((13)C-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-(13)C] lactate, which provided qualitative information regarding the lactate uptake and metabolism. The (13)C-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. Public Library of Science 2019-06-10 /pmc/articles/PMC6557470/ /pubmed/31181081 http://dx.doi.org/10.1371/journal.pone.0213419 Text en © 2019 Brodsky et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Brodsky, Arthur Nathan
Odenwelder, Daniel C.
Harcum, Sarah W.
High extracellular lactate causes reductive carboxylation in breast tissue cell lines grown under normoxic conditions
title High extracellular lactate causes reductive carboxylation in breast tissue cell lines grown under normoxic conditions
title_full High extracellular lactate causes reductive carboxylation in breast tissue cell lines grown under normoxic conditions
title_fullStr High extracellular lactate causes reductive carboxylation in breast tissue cell lines grown under normoxic conditions
title_full_unstemmed High extracellular lactate causes reductive carboxylation in breast tissue cell lines grown under normoxic conditions
title_short High extracellular lactate causes reductive carboxylation in breast tissue cell lines grown under normoxic conditions
title_sort high extracellular lactate causes reductive carboxylation in breast tissue cell lines grown under normoxic conditions
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6557470/
https://www.ncbi.nlm.nih.gov/pubmed/31181081
http://dx.doi.org/10.1371/journal.pone.0213419
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