Modeling the role of HIF in the regulation of metabolic key genes LDH and PDH: Emergence of Warburg phenotype
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 p...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2022-09-01
|
| Series: | Computational and Systems Oncology |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/cso2.1040 |
| _version_ | 1811204154646855680 |
|---|---|
| author | Kévin Spinicci Pierre Jacquet Gibin Powathil Angélique Stéphanou |
| author_facet | Kévin Spinicci Pierre Jacquet Gibin Powathil Angélique Stéphanou |
| author_sort | Kévin Spinicci |
| collection | DOAJ |
| description | 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 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. |
| first_indexed | 2024-04-12T03:06:39Z |
| format | Article |
| id | doaj.art-c634d21f54374d9383479d9ca847e51b |
| institution | Directory Open Access Journal |
| issn | 2689-9655 |
| language | English |
| last_indexed | 2024-04-12T03:06:39Z |
| publishDate | 2022-09-01 |
| publisher | Wiley |
| record_format | Article |
| series | Computational and Systems Oncology |
| spelling | doaj.art-c634d21f54374d9383479d9ca847e51b2022-12-22T03:50:29ZengWileyComputational and Systems Oncology2689-96552022-09-0123n/an/a10.1002/cso2.1040Modeling the role of HIF in the regulation of metabolic key genes LDH and PDH: Emergence of Warburg phenotypeKévin Spinicci0Pierre Jacquet1Gibin Powathil2Angélique Stéphanou3Université Grenoble Alpes CNRS UMR 5525, VetAgro Sup, Grenoble INP, TIMC Grenoble FranceUniversité Grenoble Alpes CNRS UMR 5525, VetAgro Sup, Grenoble INP, TIMC Grenoble FranceDepartment of Mathematics Swansea University Swansea UKUniversité Grenoble Alpes CNRS UMR 5525, VetAgro Sup, Grenoble INP, TIMC Grenoble FranceAbstract 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.https://doi.org/10.1002/cso2.1040hypoxia‐inducible factormetabolismmathematical modelingWarburg effect |
| spellingShingle | Kévin Spinicci Pierre Jacquet Gibin Powathil Angélique Stéphanou Modeling the role of HIF in the regulation of metabolic key genes LDH and PDH: Emergence of Warburg phenotype Computational and Systems Oncology hypoxia‐inducible factor metabolism mathematical modeling Warburg effect |
| title | 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_short | 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 |
| topic | hypoxia‐inducible factor metabolism mathematical modeling Warburg effect |
| url | https://doi.org/10.1002/cso2.1040 |
| work_keys_str_mv | AT kevinspinicci modelingtheroleofhifintheregulationofmetabolickeygenesldhandpdhemergenceofwarburgphenotype AT pierrejacquet modelingtheroleofhifintheregulationofmetabolickeygenesldhandpdhemergenceofwarburgphenotype AT gibinpowathil modelingtheroleofhifintheregulationofmetabolickeygenesldhandpdhemergenceofwarburgphenotype AT angeliquestephanou modelingtheroleofhifintheregulationofmetabolickeygenesldhandpdhemergenceofwarburgphenotype |