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Modeling the role of HIF in the regulation of metabolic key genes LDH and PDH: Emergence of Warburg phenotype

KEVIN SPINICCI, Pierre Jacquet, Gibin Powathil Orcid Logo, Angélique Stéphanou

Computational and Systems Oncology, Volume: 2, Issue: 3

Swansea University Authors: KEVIN SPINICCI, Gibin Powathil Orcid Logo

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DOI (Published version): 10.1002/cso2.1040

Abstract

Oxygenation of tumors and the effect of hypoxia on cancer cell metabolism is a widely studied subject. Hypoxia-inducible factor (HIF), the main actor in the cell response to hypoxia, represents a potential target in cancer therapy. HIF is involved in many biological processes such as cell proliferat...

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Published in: Computational and Systems Oncology
ISSN: 2689-9655 2689-9655
Published: Wiley 2022
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URI: https://cronfa.swan.ac.uk/Record/cronfa60373
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Hypoxia-inducible factor (HIF), the main actor in the cell response to hypoxia, represents a potential target in cancer therapy. HIF is involved in many biological processes such as cell proliferation, survival, apoptosis, angiogenesis, iron metabolism, and glucose metabolism. This protein regulates the expressions of lactate dehydrogenase (LDH) and pyruvate dehydrogenase (PDH), both essential for the conversion of pyruvate to be used in aerobic and anaerobic pathways. HIF upregulates LDH, increasing the conversion of pyruvate into lactate which leads to higher secretion of lactic acid by the cell and reduced pH in the microenvironment. HIF indirectly downregulates PDH, decreasing the conversion of pyruvate into acetyl coenzyme A, which leads to reduced usage of the tricarboxylic acid (TCA) cycle in aerobic pathways. Upregulation of HIF may promote the use of anaerobic pathways for energy production even in normal extracellular oxygen conditions. Higher use of glycolysis even in normal oxygen conditions is called the Warburg effect. In this paper, we focus on HIF variations during tumor growth and study, through a mathematical model, its impact on the two metabolic key genes PDH and LDH, to investigate its role in the emergence of the Warburg effect. Mathematical equations describing the enzyme regulation pathways were solved for each cell of the tumor represented in an agent-based model to best capture the spatio-temporal oxygen variations during tumor development caused by cell consumption and reduced diffusion inside the tumor. Simulation results show that reduced HIF degradation in normoxia can induce higher lactic acid production. The emergence of the Warburg effect appears after the first period of hypoxia before oxygen conditions return to a normal level. 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spelling 2022-10-27T11:54:46.4103092 v2 60373 2022-07-04 Modeling the role of HIF in the regulation of metabolic key genes LDH and PDH: Emergence of Warburg phenotype a1c53ecd60a1e5c342e2bdaa93461c12 KEVIN SPINICCI KEVIN SPINICCI true false f23646a94239f673e2a43ebe7397aabd 0000-0002-8372-7349 Gibin Powathil Gibin Powathil true false 2022-07-04 Oxygenation of tumors and the effect of hypoxia on cancer cell metabolism is a widely studied subject. Hypoxia-inducible factor (HIF), the main actor in the cell response to hypoxia, represents a potential target in cancer therapy. HIF is involved in many biological processes such as cell proliferation, survival, apoptosis, angiogenesis, iron metabolism, and glucose metabolism. This protein regulates the expressions of lactate dehydrogenase (LDH) and pyruvate dehydrogenase (PDH), both essential for the conversion of pyruvate to be used in aerobic and anaerobic pathways. HIF upregulates LDH, increasing the conversion of pyruvate into lactate which leads to higher secretion of lactic acid by the cell and reduced pH in the microenvironment. HIF indirectly downregulates PDH, decreasing the conversion of pyruvate into acetyl coenzyme A, which leads to reduced usage of the tricarboxylic acid (TCA) cycle in aerobic pathways. Upregulation of HIF may promote the use of anaerobic pathways for energy production even in normal extracellular oxygen conditions. Higher use of glycolysis even in normal oxygen conditions is called the Warburg effect. In this paper, we focus on HIF variations during tumor growth and study, through a mathematical model, its impact on the two metabolic key genes PDH and LDH, to investigate its role in the emergence of the Warburg effect. Mathematical equations describing the enzyme regulation pathways were solved for each cell of the tumor represented in an agent-based model to best capture the spatio-temporal oxygen variations during tumor development caused by cell consumption and reduced diffusion inside the tumor. Simulation results show that reduced HIF degradation in normoxia can induce higher lactic acid production. The emergence of the Warburg effect appears after the first period of hypoxia before oxygen conditions return to a normal level. The results also show that targeting the upregulation of LDH and the downregulation of PDH could be relevant in therapy. Journal Article Computational and Systems Oncology 2 3 Wiley 2689-9655 2689-9655 hypoxia-inducible factor, metabolism, mathematical modeling, Warburg effect 1 9 2022 2022-09-01 10.1002/cso2.1040 COLLEGE NANME COLLEGE CODE Swansea University SU Library paid the OA fee (TA Institutional Deal) Centre National de la RechercheScientifique (MITI interdisciplinaryprogram); Swansea University; IDEXUniversité Grenoble Alpes 2022-10-27T11:54:46.4103092 2022-07-04T11:25:59.8154067 Faculty of Science and Engineering School of Mathematics and Computer Science - Mathematics KEVIN SPINICCI 1 Pierre Jacquet 2 Gibin Powathil 0000-0002-8372-7349 3 Angélique Stéphanou 4 60373__25048__33d92f76255f47dab958587b54619efb.pdf 60373_VoR.pdf 2022-08-30T15:39:58.4583415 Output 3542955 application/pdf Version of Record true © 2022 The Authors. This is an open access article under the terms of the Creative Commons Attribution License true eng http://creativecommons.org/licenses/by/4.0/
title Modeling the role of HIF in the regulation of metabolic key genes LDH and PDH: Emergence of Warburg phenotype
spellingShingle Modeling the role of HIF in the regulation of metabolic key genes LDH and PDH: Emergence of Warburg phenotype
KEVIN SPINICCI
Gibin Powathil
title_short Modeling the role of HIF in the regulation of metabolic key genes LDH and PDH: Emergence of Warburg phenotype
title_full Modeling the role of HIF in the regulation of metabolic key genes LDH and PDH: Emergence of Warburg phenotype
title_fullStr Modeling the role of HIF in the regulation of metabolic key genes LDH and PDH: Emergence of Warburg phenotype
title_full_unstemmed Modeling the role of HIF in the regulation of metabolic key genes LDH and PDH: Emergence of Warburg phenotype
title_sort Modeling the role of HIF in the regulation of metabolic key genes LDH and PDH: Emergence of Warburg phenotype
author_id_str_mv a1c53ecd60a1e5c342e2bdaa93461c12
f23646a94239f673e2a43ebe7397aabd
author_id_fullname_str_mv a1c53ecd60a1e5c342e2bdaa93461c12_***_KEVIN SPINICCI
f23646a94239f673e2a43ebe7397aabd_***_Gibin Powathil
author KEVIN SPINICCI
Gibin Powathil
author2 KEVIN SPINICCI
Pierre Jacquet
Gibin Powathil
Angélique Stéphanou
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container_title Computational and Systems Oncology
container_volume 2
container_issue 3
publishDate 2022
institution Swansea University
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doi_str_mv 10.1002/cso2.1040
publisher Wiley
college_str Faculty of Science and Engineering
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hierarchy_top_id facultyofscienceandengineering
hierarchy_top_title Faculty of Science and Engineering
hierarchy_parent_id facultyofscienceandengineering
hierarchy_parent_title Faculty of Science and Engineering
department_str School of Mathematics and Computer Science - Mathematics{{{_:::_}}}Faculty of Science and Engineering{{{_:::_}}}School of Mathematics and Computer Science - Mathematics
document_store_str 1
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description Oxygenation of tumors and the effect of hypoxia on cancer cell metabolism is a widely studied subject. Hypoxia-inducible factor (HIF), the main actor in the cell response to hypoxia, represents a potential target in cancer therapy. HIF is involved in many biological processes such as cell proliferation, survival, apoptosis, angiogenesis, iron metabolism, and glucose metabolism. This protein regulates the expressions of lactate dehydrogenase (LDH) and pyruvate dehydrogenase (PDH), both essential for the conversion of pyruvate to be used in aerobic and anaerobic pathways. HIF upregulates LDH, increasing the conversion of pyruvate into lactate which leads to higher secretion of lactic acid by the cell and reduced pH in the microenvironment. HIF indirectly downregulates PDH, decreasing the conversion of pyruvate into acetyl coenzyme A, which leads to reduced usage of the tricarboxylic acid (TCA) cycle in aerobic pathways. Upregulation of HIF may promote the use of anaerobic pathways for energy production even in normal extracellular oxygen conditions. Higher use of glycolysis even in normal oxygen conditions is called the Warburg effect. In this paper, we focus on HIF variations during tumor growth and study, through a mathematical model, its impact on the two metabolic key genes PDH and LDH, to investigate its role in the emergence of the Warburg effect. Mathematical equations describing the enzyme regulation pathways were solved for each cell of the tumor represented in an agent-based model to best capture the spatio-temporal oxygen variations during tumor development caused by cell consumption and reduced diffusion inside the tumor. Simulation results show that reduced HIF degradation in normoxia can induce higher lactic acid production. The emergence of the Warburg effect appears after the first period of hypoxia before oxygen conditions return to a normal level. The results also show that targeting the upregulation of LDH and the downregulation of PDH could be relevant in therapy.
published_date 2022-09-01T04:18:25Z
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