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A metabolic core model elucidates how enhanced utilization of glucose and glutamine, with enhanced glutamine-dependent lactate production, promotes cancer cell growth
- Source :
- PLoS Computational Biology, PLoS Computational Biology, Vol 13, Iss 9, p e1005758 (2017), PLoS Computational Biology, 13(9):e1005758. Public Library of Science, Damiani, C, Colombo, R, Gaglio, D, Mastroianni, F, Pescini, D, Westerhoff, H V, Mauri, G, Vanoni, M & Alberghina, L 2017, ' A metabolic core model elucidates how enhanced utilization of glucose and glutamine, with enhanced glutamine-dependent lactate production, promotes cancer cell growth : The WarburQ effect ', PLoS Computational Biology, vol. 13, no. 9, e1005758 . https://doi.org/10.1371/journal.pcbi.1005758, Damiani, C, Colombo, R, Gaglio, D, Mastroianni, F, Pescini, D, Westerhoff, H V, Mauri, G, Vanoni, M & Alberghina, L 2017, ' A metabolic core model elucidates how enhanced utilization of glucose and glutamine, with enhanced glutamine-dependent lactate production, promotes cancer cell growth : The WarburQ effect ', PLoS computational biology, vol. 13, no. 9, e1005758 . https://doi.org/10.1371/journal.pcbi.1005758, PLOS Computational Biology, PLoS computational biology 13 (2017): e1005758. doi:10.1371/journal.pcbi.1005758, info:cnr-pdr/source/autori:Damiani, Chiara; Damiani, Chiara; Colombo, Riccardo; Colombo, Riccardo; Gaglio, Daniela; Gaglio, Daniela; Mastroianni, Fabrizia; Mastroianni, Fabrizia; Pescini, Dario; Pescini, Dario; Westerhoff, Hans Victor; Westerhoff, Hans Victor; Westerhoff, Hans Victor; Mauri, Giancarlo; Mauri, Giancarlo; Vanoni, Marco; Vanoni, Marco; Alberghina, Lilia; Alberghina, Lilia/titolo:A metabolic core model elucidates how enhanced utilization of glucose and glutamine, with enhanced glutamine-dependent lactate production, promotes cancer cell growth: The WarburQ effect/doi:10.1371%2Fjournal.pcbi.1005758/rivista:PLoS computational biology/anno:2017/pagina_da:e1005758/pagina_a:/intervallo_pagine:e1005758/volume:13
- Publication Year :
- 2017
- Publisher :
- Public Library of Science, 2017.
-
Abstract
- Cancer cells share several metabolic traits, including aerobic production of lactate from glucose (Warburg effect), extensive glutamine utilization and impaired mitochondrial electron flow. It is still unclear how these metabolic rearrangements, which may involve different molecular events in different cells, contribute to a selective advantage for cancer cell proliferation. To ascertain which metabolic pathways are used to convert glucose and glutamine to balanced energy and biomass production, we performed systematic constraint-based simulations of a model of human central metabolism. Sampling of the feasible flux space allowed us to obtain a large number of randomly mutated cells simulated at different glutamine and glucose uptake rates. We observed that, in the limited subset of proliferating cells, most displayed fermentation of glucose to lactate in the presence of oxygen. At high utilization rates of glutamine, oxidative utilization of glucose was decreased, while the production of lactate from glutamine was enhanced. This emergent phenotype was observed only when the available carbon exceeded the amount that could be fully oxidized by the available oxygen. Under the latter conditions, standard Flux Balance Analysis indicated that: this metabolic pattern is optimal to maximize biomass and ATP production; it requires the activity of a branched TCA cycle, in which glutamine-dependent reductive carboxylation cooperates to the production of lipids and proteins; it is sustained by a variety of redox-controlled metabolic reactions. In a K-ras transformed cell line we experimentally assessed glutamine-induced metabolic changes. We validated computational results through an extension of Flux Balance Analysis that allows prediction of metabolite variations. Taken together these findings offer new understanding of the logic of the metabolic reprogramming that underlies cancer cell growth.<br />Author summary Hallmarks describing common key events in initiation, maintenance and progression of cancer have been identified. One hallmark deals with rewiring of metabolic reactions required to sustain enhanced cell proliferation. The availability of molecular, mechanistic models of cancer hallmarks will mightily improve optimized personal treatment and new drug discovery. Metabolism is the only hallmark for which it is currently possible to derive large scale mathematical models, which have predictive ability. In this paper, we exploit a constraint-based model of the core metabolism required for biomass conversion of the most relevant nutrients—glucose and glutamine—to clarify the logic of control of cancer metabolism. We newly report that, when available oxygen is not sufficient to fully oxidize available glucose and glutamine carbons–a situation compatible with that observed under normal oxygen conditions in human and in cancer cells growing in vitro—utilization of glutamine by reductive carboxylation and conversion of glucose and glutamine to lactate confer advantage for biomass production. Redox homeostasis can be maintained through the use of different alternative pathways. In conclusion, this paper offers a logic interpretation to the link between metabolic rewiring and enhanced proliferation, which may offer new approaches to targeted drug discovery and utilization.
- Subjects :
- Metabolic Processes
0301 basic medicine
Glucose uptake
Glutamine
Biochemistry
7. Clean energy
Glucose Metabolism
Drug Metabolism
Metabolic Flux Analysi
Neoplasms
Metabolic flux analysis
Medicine and Health Sciences
Amino Acids
lcsh:QH301-705.5
Ecology
Organic Compounds
Acidic Amino Acids
Monosaccharides
Ketones
Enzymes
Flux balance analysis
Chemistry
Computational Theory and Mathematics
Modeling and Simulation
Physical Sciences
Carbohydrate Metabolism
Oxidoreductases
Metabolic Networks and Pathways
Research Article
Chemical Elements
Human
Pyruvate
Citric Acid Cycle
Carbohydrates
Biology
Models, Biological
03 medical and health sciences
Cellular and Molecular Neuroscience
Genetic
Manchester Institute of Biotechnology
Genetics
Animals
Humans
Pharmacokinetics
Computer Simulation
Lactic Acid
Molecular Biology
Dehydrogenases
Ecology, Evolution, Behavior and Systematics
Cell Proliferation
Pharmacology
Organic Chemistry
Chemical Compounds
Biology and Life Sciences
Proteins
Metabolic Networks and Pathway
Metabolism
ResearchInstitutes_Networks_Beacons/manchester_institute_of_biotechnology
Metabolic Flux Analysis
Oxygen
Citric acid cycle
Metabolic pathway
030104 developmental biology
Glucose
lcsh:Biology (General)
Enzymology
Acids
Flux (metabolism)
Subjects
Details
- Language :
- English
- ISSN :
- 15537358 and 1553734X
- Volume :
- 13
- Issue :
- 9
- Database :
- OpenAIRE
- Journal :
- PLoS Computational Biology
- Accession number :
- edsair.doi.dedup.....c611158ec7fcc605301dbac92968ba93