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Activation of Toll-like receptor 2 via specific agonists promotes OXPHOS and glycolysis in gastric cancer cells rather than other Toll-like receptors


 Background

Toll-like receptor (TLR)2 activation via microbial and host stimuli plays important roles in the regulation of metabolic reprogramming in immune cells. We recently showed that ligand-induced TLR2 activation enhanced OXPHOS and glycolytic activity of gastric epithelial (cancer) cells, thus promoting tumour progression.
Objective

To investigate the full spectrum of TLR family members whose ligand-dependent activation can cause metabolic reprogramming in gastric cancer (GC) cells.
Methods

The expression of TLR family members was measured by RT-qPCR and Western blotting in a panel of human GC cells. Metabolic changes in human GC cells which were induced by agonists for different TLRs (TLR2, 4, 9) were identified by performing the Seahorse bioenergetic assay, as well as by measuring L-lactate and ROS production. The expression of genes involved in oxidative phosphorylation and glycolysis was also profiled in stimulated GC cells by RT-qPCR. Western blot further characterized the expression of SOD2, a key downstream target of TLR2 signaling in GC.
Results

TLR2 signaling activated by either synthetic molecules or whole pathogen antigen enhanced glycolytic activity and mitochondrial respiration in TLR2-high expressing cells, whereas ligand-induced TLR4 and TLR9 activation inhibited mitochondrial respiration or extracellular acidification rate. Furthermore, genes implicated in the regulation of glucose metabolism and the redox system, such as HIF1A, PFKFB3 and SOD2, were upregulated downstream of TLRs.
Conclusion

Our study reveals that ligand-induced activation of specific TLRs mediates diverse metabolic phenotype in human GC cells. TLR2 is the only family member that promotes both OXPHOS and glycolysis, which may result in tumor progression.