Metabolic Constants and Plasticity of Cancer Cells in a Limiting Glucose and Glutamine Microenvironment—A Pyruvate Perspective
The metabolism of cancer cells is an issue of dealing with fluctuating and limiting levels of nutrients in a precarious microenvironment to ensure their vitality and propagation. Glucose and glutamine are central metabolites for catabolic and anabolic metabolism, which is in the limelight of numerou...
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| Published in: | Frontiers in oncology Vol. 10; p. 596197 |
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| Format: | Journal Article |
| Language: | English |
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08.12.2020
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| ISSN: | 2234-943X, 2234-943X |
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| Abstract | The metabolism of cancer cells is an issue of dealing with fluctuating and limiting levels of nutrients in a precarious microenvironment to ensure their vitality and propagation. Glucose and glutamine are central metabolites for catabolic and anabolic metabolism, which is in the limelight of numerous diagnostic methods and therapeutic targeting. Understanding tumor metabolism in conditions of nutrient depletion is important for such applications and for interpreting the readouts. To exemplify the metabolic network of tumor cells in a model system, the fate
13
C
6
-glucose was tracked in a breast cancer cell line growing in variable low glucose/low glutamine conditions.
13
C-glucose-derived metabolites allowed to deduce the engagement of metabolic pathways, namely glycolysis, the TCA-cycle including glutamine and pyruvate anaplerosis, amino acid synthesis (serine, glycine, aspartate, glutamate), gluconeogenesis, and pyruvate replenishment. While the metabolic program did not change, limiting glucose and glutamine supply reduced cellular metabolite levels and enhanced pyruvate recycling as well as pyruvate carboxylation for entry into the TCA-cycle. Otherwise, the same metabolic pathways, including gluconeogenesis, were similarly engaged with physiologically saturating as with limiting glucose and glutamine. Therefore, the metabolic plasticity in precarious nutritional microenvironment does not require metabolic reprogramming, but is based on dynamic changes in metabolite quantity, reaction rates, and directions of the existing metabolic network. |
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| AbstractList | The metabolism of cancer cells is an issue of dealing with fluctuating and limiting levels of nutrients in a precarious microenvironment to ensure their vitality and propagation. Glucose and glutamine are central metabolites for catabolic and anabolic metabolism, which is in the limelight of numerous diagnostic methods and therapeutic targeting. Understanding tumor metabolism in conditions of nutrient depletion is important for such applications and for interpreting the readouts. To exemplify the metabolic network of tumor cells in a model system, the fate
13
C
6
-glucose was tracked in a breast cancer cell line growing in variable low glucose/low glutamine conditions.
13
C-glucose-derived metabolites allowed to deduce the engagement of metabolic pathways, namely glycolysis, the TCA-cycle including glutamine and pyruvate anaplerosis, amino acid synthesis (serine, glycine, aspartate, glutamate), gluconeogenesis, and pyruvate replenishment. While the metabolic program did not change, limiting glucose and glutamine supply reduced cellular metabolite levels and enhanced pyruvate recycling as well as pyruvate carboxylation for entry into the TCA-cycle. Otherwise, the same metabolic pathways, including gluconeogenesis, were similarly engaged with physiologically saturating as with limiting glucose and glutamine. Therefore, the metabolic plasticity in precarious nutritional microenvironment does not require metabolic reprogramming, but is based on dynamic changes in metabolite quantity, reaction rates, and directions of the existing metabolic network. The metabolism of cancer cells is an issue of dealing with fluctuating and limiting levels of nutrients in a precarious microenvironment to ensure their vitality and propagation. Glucose and glutamine are central metabolites for catabolic and anabolic metabolism, which is in the limelight of numerous diagnostic methods and therapeutic targeting. Understanding tumor metabolism in conditions of nutrient depletion is important for such applications and for interpreting the readouts. To exemplify the metabolic network of tumor cells in a model system, the fate 13C6-glucose was tracked in a breast cancer cell line growing in variable low glucose/low glutamine conditions. 13C-glucose-derived metabolites allowed to deduce the engagement of metabolic pathways, namely glycolysis, the TCA-cycle including glutamine and pyruvate anaplerosis, amino acid synthesis (serine, glycine, aspartate, glutamate), gluconeogenesis, and pyruvate replenishment. While the metabolic program did not change, limiting glucose and glutamine supply reduced cellular metabolite levels and enhanced pyruvate recycling as well as pyruvate carboxylation for entry into the TCA-cycle. Otherwise, the same metabolic pathways, including gluconeogenesis, were similarly engaged with physiologically saturating as with limiting glucose and glutamine. Therefore, the metabolic plasticity in precarious nutritional microenvironment does not require metabolic reprogramming, but is based on dynamic changes in metabolite quantity, reaction rates, and directions of the existing metabolic network. The metabolism of cancer cells is an issue of dealing with fluctuating and limiting levels of nutrients in a precarious microenvironment to ensure their vitality and propagation. Glucose and glutamine are central metabolites for catabolic and anabolic metabolism, which is in the limelight of numerous diagnostic methods and therapeutic targeting. Understanding tumor metabolism in conditions of nutrient depletion is important for such applications and for interpreting the readouts. To exemplify the metabolic network of tumor cells in a model system, the fate C -glucose was tracked in a breast cancer cell line growing in variable low glucose/low glutamine conditions. C-glucose-derived metabolites allowed to deduce the engagement of metabolic pathways, namely glycolysis, the TCA-cycle including glutamine and pyruvate anaplerosis, amino acid synthesis (serine, glycine, aspartate, glutamate), gluconeogenesis, and pyruvate replenishment. While the metabolic program did not change, limiting glucose and glutamine supply reduced cellular metabolite levels and enhanced pyruvate recycling as well as pyruvate carboxylation for entry into the TCA-cycle. Otherwise, the same metabolic pathways, including gluconeogenesis, were similarly engaged with physiologically saturating as with limiting glucose and glutamine. Therefore, the metabolic plasticity in precarious nutritional microenvironment does not require metabolic reprogramming, but is based on dynamic changes in metabolite quantity, reaction rates, and directions of the existing metabolic network. The metabolism of cancer cells is an issue of dealing with fluctuating and limiting levels of nutrients in a precarious microenvironment to ensure their vitality and propagation. Glucose and glutamine are central metabolites for catabolic and anabolic metabolism, which is in the limelight of numerous diagnostic methods and therapeutic targeting. Understanding tumor metabolism in conditions of nutrient depletion is important for such applications and for interpreting the readouts. To exemplify the metabolic network of tumor cells in a model system, the fate 13C6-glucose was tracked in a breast cancer cell line growing in variable low glucose/low glutamine conditions. 13C-glucose-derived metabolites allowed to deduce the engagement of metabolic pathways, namely glycolysis, the TCA-cycle including glutamine and pyruvate anaplerosis, amino acid synthesis (serine, glycine, aspartate, glutamate), gluconeogenesis, and pyruvate replenishment. While the metabolic program did not change, limiting glucose and glutamine supply reduced cellular metabolite levels and enhanced pyruvate recycling as well as pyruvate carboxylation for entry into the TCA-cycle. Otherwise, the same metabolic pathways, including gluconeogenesis, were similarly engaged with physiologically saturating as with limiting glucose and glutamine. Therefore, the metabolic plasticity in precarious nutritional microenvironment does not require metabolic reprogramming, but is based on dynamic changes in metabolite quantity, reaction rates, and directions of the existing metabolic network.The metabolism of cancer cells is an issue of dealing with fluctuating and limiting levels of nutrients in a precarious microenvironment to ensure their vitality and propagation. Glucose and glutamine are central metabolites for catabolic and anabolic metabolism, which is in the limelight of numerous diagnostic methods and therapeutic targeting. Understanding tumor metabolism in conditions of nutrient depletion is important for such applications and for interpreting the readouts. To exemplify the metabolic network of tumor cells in a model system, the fate 13C6-glucose was tracked in a breast cancer cell line growing in variable low glucose/low glutamine conditions. 13C-glucose-derived metabolites allowed to deduce the engagement of metabolic pathways, namely glycolysis, the TCA-cycle including glutamine and pyruvate anaplerosis, amino acid synthesis (serine, glycine, aspartate, glutamate), gluconeogenesis, and pyruvate replenishment. While the metabolic program did not change, limiting glucose and glutamine supply reduced cellular metabolite levels and enhanced pyruvate recycling as well as pyruvate carboxylation for entry into the TCA-cycle. Otherwise, the same metabolic pathways, including gluconeogenesis, were similarly engaged with physiologically saturating as with limiting glucose and glutamine. Therefore, the metabolic plasticity in precarious nutritional microenvironment does not require metabolic reprogramming, but is based on dynamic changes in metabolite quantity, reaction rates, and directions of the existing metabolic network. |
| Author | Otto, Angela M. |
| AuthorAffiliation | Munich School of BioEngineering, Technical University of Munich , Garching , Germany |
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| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/33425750$$D View this record in MEDLINE/PubMed |
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| Cites_doi | 10.1111/j.1432-1033.1982.tb05851.x 10.1111/eva.12015 10.1208/s12248-008-9022-y 10.1002/mc.2940080112 10.1038/nature10350 10.1038/nrc.2016.81 10.1016/j.ymben.2017.02.002 10.1016/j.cell.2016.12.039 10.1158/0008-5472.CAN-09-3556 10.1016/j.cell.2011.02.013 10.1007/s11306-007-0094-y 10.1007/BF01372723 10.1007/BF00396375 10.1016/j.molcel.2015.08.013 10.1083/jcb.200703099 10.1111/febs.12864 10.1016/0005-2744(71)90211-7 10.3390/cells8101113 10.1038/nature11540 10.1016/j.cmet.2011.12.009 10.1016/j.cels.2018.06.003 10.1016/j.molcel.2014.09.024 10.1016/j.copbio.2015.02.003 10.1042/bj1480085 10.1016/j.bbadis.2016.11.021 10.2174/1574892811308010085 10.1002/jcb.25038 10.1073/pnas.70.6.1775 10.3892/ijmm_00000173 10.1074/jbc.271.25.14883 10.1016/j.molcel.2015.09.025 10.1042/bj1900705 10.1186/s12964-019-0332-8 10.1074/jbc.RA119.009093 10.1073/pnas.93.5.1847 10.1079/BJN2001454 10.4161/cc.9.19.13302 10.1016/j.bbcan.2012.07.001 10.1074/jbc.M114.566927 10.1002/glia.1054 10.1016/j.biochi.2015.09.017 10.1038/msb.2011.56 10.1038/onc.2014.47 10.1016/j.tcb.2017.05.001 10.4161/cc.9.24.14230 |
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| Keywords | pyruvate replenishment 13C-glucose tracing TCA-cycle anaplerosis nutrient deprivation glycolysis glutamine metabolic network |
| Language | English |
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| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 ObjectType-Review-3 content type line 23 This article was submitted to Cancer Metabolism, a section of the journal Frontiers in Oncology Reviewed by: Khalid Omer Alfarouk, Alfarouk Biomedical Research LLC, United States; Angela Ostuni, University of Basilicata, Italy Edited by: Fatima Baltazar, University of Minho, Portugal |
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| SubjectTerms | 13C-glucose tracing anaplerosis glutamine glycolysis nutrient deprivation Oncology TCA-cycle |
| Title | Metabolic Constants and Plasticity of Cancer Cells in a Limiting Glucose and Glutamine Microenvironment—A Pyruvate Perspective |
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