Investigating the Role of the PGE2-EP4 Axis in Colorectal Tumour Cell Metabolism

Abstract

Prostaglandin E2 (PGE2) is an inflammatory lipid signalling molecule, involved in many important physiological processes such as tissue regeneration and repair. PGE2 is also known to drive tumorigenesis and progression of colorectal cancer (CRC), mainly by signalling through the EP4 G-protein coupled receptor. When deregulated, the PGE2-EP4 signalling axis can promote many ‘hallmarks of cancer’. Although inhibition of cyclooxygenase enzymes, responsible for PGE2 synthesis, has limited clinical use for CRC prevention (due to adverse side effects), EP4 receptor-specific antagonists have been developed to provide a more targeted approach. To further understand their potential for use in CRC prevention, the aim of this project was to investigate the effect of PGE2-EP4 signalling on metabolic reprogramming in colorectal tumour cells, required to support tumour growth.
Results presented here demonstrate the efficacy of the EP4 antagonists E7046 and HTL0039732 in suppressing PGE2-driven growth of human colorectal adenoma-derived cells and organoid models of colorectal tumour progression. Proteomic analysis identified that metabolic processes are highly regulated by PGE2 in colorectal adenoma cells, with significant upregulation of glycolytic enzymes, most notably Aldolase B (ALDOB). Correspondingly, extracellular flux analysis showed that PGE2 increases activity of glycolysis and oxidative phosphorylation pathways. Furthermore, stable isotope tracer analyses revealed that PGE2 enhances both glucose and fructose utilisation; results suggest that this is due to PGE2-driven upregulation of ALDOB in these premalignant tumour cells. These findings identify a novel role of PGE2 in colorectal tumour cell metabolism and illustrate the significance of fructose metabolism in promoting colorectal tumour growth. Importantly, the observed metabolic effects of PGE2 are inhibited by EP4 antagonists E7046 and HTL0039732, indicating that these effects occur via EP4 receptor activation. This highlights an exciting potential clinical use of these EP4 antagonists for chemoprevention in individuals at high risk of developing CRC, or as a therapeutic strategy.

Date of Award	17 Mar 2026
Original language	English
Awarding Institution	University of Bristol
Supervisor	Emma E Vincent (Supervisor) & Ann Williams (Supervisor)