Esculin Facilitates Aerobic Glycolysis via the Wnt/β-Catenin/HIF-1α Pathway to Reduce the Progression of Gastric Cancer.

[BACKGROUND] Gastric cancer (GC) is a complex pathogenesis closely related to various signalling pathways. Esculin, as a natural compound, possesses anti-oxidation, anti-inflammatory, and anti-tumour influences, and has shown promising application prospects in research on colorectal cancer (CRC) and others. However, the specific impact of Esculin on GC remains unclear. This article explores the action mechanism of Esculin in gastric cancer, which not only helps to understand its anti-cancer properties but may also offer novel approaches and strategies for treating GC.

[METHODS] Using the CCK-8 method to screen the concentration of Esculin that does not affect the viability of normal gastric mucosal cells GES-1. At this concentration, the changes in viability, proliferation level, migration ability, invasion ability, and apoptosis level of HGC-27 and AGS were measured. The levels of related proteins were detected through Western blot. Subsequent use of the glycolysis inhibitor 3-BrPA, the Wnt signalling pathway activator SKL2001, and the inhibitor LiCl interfered with GC cells. The impact of Esculin on aerobic glycolysis in cells was assessed by measuring glucose uptake levels, pyruvate production levels, lactate generation levels, ATP production levels, and extracellular acidification rate (ECAR). The regulatory effect of Esculin on the Wnt/β-catenin/HIF-1α pathway was evaluated through immunofluorescence and Western blot. Injecting HGC-27 cells to build a xenograft tumour model and evaluating the effect of Esculin gavage on tumour growth in mice.

[RESULTS] Esculin at concentrations of 0, 20, 40, and 80 μM is non-toxic to GES-1. An increase in the concentration of Esculin correlates with a continuous decline in the viability of four GC cell lines, with GC cells showing the highest significance. The levels of proliferation, migration, and invasion in both cell lines significantly decrease with increasing concentrations of Esculin, while the apoptosis rate significantly increases. 80 μM of Esculin can significantly inhibit glucose absorption, pyruvate production, lactate, and ATP generation in cells, leading to a significant decrease in ECAR; at the same time, it significantly inhibits the expression of proteins in the Wnt/β-catenin/HIF-1α signalling pathway. Administering 20 mg/kg of Esculin by gavage can significantly suppress tumour growth in mice, concurrently leading to a reduction of proteins associated with the Wnt/β-catenin/HIF-1α pathway within the tumour tissue.

[CONCLUSION] Esculin inhibits aerobic glycolysis in cells via the Wnt/β-catenin/HIF-1α pathway, alleviating the progress of GC.