Pseudomonas aeruginosa metabolite 3-oxo-C12HSL induces apoptosis through T2R14 and the mitochondrial calcium uniporter

Head and neck squamous cell carcinomas (HNSCCs) arise in the mucosal lining of the upper aerodigestive tract. HNSCCs have high mortality rates and current treatments can be associated with severe morbidities. It is vital to discover effective, minimally invasive therapies that improve survival and quality of life. We previously discovered that bitter taste receptor 14 (T2R14), a GPCR, kills HNSCC cells when activated by bitter agonists. We are now investigating endogenous bitter ligands that exist in HNSCC tumor microenvironment (TME). The TME includes cells, signaling molecules, and microbes that can greatly influence treatment responses and overall prognosis in HNSCC. Pseudomonas aeruginosa is a gram-negative bacterium that colonizes/infects HNSCC patients. 3-oxo-C12SHL is a quorum-sensing N-acyl homoserine lactone (AHL) secreted by P. aeruginosa which is also a bitter compound. 3-oxo-C12HSL induces apoptosis but this has never been linked to T2R activation. We hypothesized that 3-oxo-C12HSL induces apoptosis in HNSCC via T2R14. We show that 3-oxo-C12HSL activates intracellular Ca ²⁺ responses in HNSCC cells. This is inhibited with T2R14 antagonization. 3-oxo-C12HSL may activate additional Ca ²⁺ channels as the Ca ²⁺ dynamics are independent from store-operated calcium entry (SOCE). 3-oxo-C12HSL inhibits cell viability, depolarizes mitochondria, and produces ROS. This induces apoptosis in HNSCC cells. In a comparative screen of quorum-sensing AHLs, 3-oxo-C12HSL was the only AHL that elicited both a Ca ²⁺ response and reduced cell viability. These results suggest that P. aeruginosa may play a significant role in modulating an anti-tumor TME through 3-oxo-C12HSL. Moreover, 3-oxo-C12HSL could be a novel, higher-affinity bitter therapeutic for HNSCC. Further research is warranted to elucidate the mechanisms of other endogenous T2R agonists present in the TME.