No Cover Image

Journal article 551 views 81 downloads

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

  • 60373_VoR.pdf

    PDF | Version of Record

    © 2022 The Authors. This is an open access article under the terms of the Creative Commons Attribution License

    Download (3.38MB)

Check full text

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...

Full description

Published in: Computational and Systems Oncology
ISSN: 2689-9655 2689-9655
Published: Wiley 2022
Online Access: Check full text

URI: https://cronfa.swan.ac.uk/Record/cronfa60373
Tags: Add Tag
No Tags, Be the first to tag this record!
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.
Keywords: hypoxia-inducible factor, metabolism, mathematical modeling, Warburg effect
College: Faculty of Science and Engineering
Funders: Centre National de la RechercheScientifique (MITI interdisciplinaryprogram); Swansea University; IDEXUniversité Grenoble Alpes
Issue: 3