Modelling the role of Hypoxia Inducible Factor in the regulation of
metabolic key genes Lactate Dehydrogenase and Pyruvate Dehydrogenase:
Emergence of Warburg Phenotype.
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 tumour 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 enzymes regulation
pathways were solved for each cell of the tumour represented in an
agent-based model to best capture the spatio-temporal oxygen variations
during tumour development caused by cell consumption and reduced
diffusion inside the tumour. 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.