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arXiv · 2404.18613

P53 Orchestrates Cancer Metabolism: Unveiling Strategies to Reverse the Warburg Effect

Roba Abukwaik·Elias Vera-Siguenza·Daniel Tennant·Fabian Spill
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Abstract

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.

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Roba Abukwaik, Elias Vera-Siguenza, Daniel Tennant, Fabian Spill. 2024-08-02. P53 Orchestrates Cancer Metabolism: Unveiling Strategies to Reverse the Warburg Effect. https://arxiv.org/abs/2404.18613

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