  Cancer cells exhibit significant alterations in their metabolism,
characterised by a reduction in oxidative phosphorylation (OXPHOS) and an
increased reliance on glycolysis, even in the presence of oxygen. This
metabolic shift, known as the Warburg effect, is pivotal in fuelling cancer's
uncontrolled growth, invasion, and therapeutic resistance. While dysregulation
of many genes contributes to this metabolic shift, the tumour suppressor gene
p53 emerges as a master player. Yet, the molecular mechanisms remain elusive.
This study introduces a comprehensive mathematical model, integrating essential
p53 targets, offering insights into how p53 orchestrates its targets to
redirect cancer metabolism towards an OXPHOS-dominant state. Simulation
outcomes align closely with experimental data comparing glucose metabolism in
colon cancer cells with wild-type and mutated p53. Additionally, our findings
reveal the dynamic capability of elevated p53 activation to fully reverse the
Warburg effect, highlighting the significance of its activity levels not just
in triggering apoptosis (programmed cell death) post-chemotherapy but also in
modifying the metabolic pathways implicated in treatment resistance. In
scenarios of p53 mutations, our analysis suggests targeting
glycolysis-instigating signalling pathways as an alternative strategy, whereas
targeting solely synthesis of cytochrome c oxidase 2 (SCO2) does support
mitochondrial respiration but may not effectively suppress the glycolysis
pathway, potentially boosting the energy production and cancer cell viability.
