Lidocaine Induces Apoptosis in Head and Neck Squamous Cell Carcinoma Cells Through Activation of Bitter Taste Receptor T2R14

Head and neck squamous cell carcinomas (HNSCCs) have high mortality and significant treatment-related morbidity. It is vital to discover effective, minimally invasive therapies that improve survival and quality of life. Bitter taste receptors (T2Rs) are expressed in HNSCCs and their activation can induce apoptosis. Lidocaine is a local anesthetic used in various clinical applications which can also activate bitter taste receptor 14 (T2R14). Lidocaine may have some anti-tumor effects in other cancers, but the mechanism has been mysterious. Here, we found that lidocaine causes intracellular Ca2+ mobilization through activation of T2R14 in HSNCC cells. T2R14 activation with lidocaine depolarizes the mitochondrial membrane, inhibits cell proliferation, and induces apoptosis. Concomitant mitochondrial Ca2+ influx, ROS production causes T2R14-dependent accumulation of poly-ubiquinated proteins, suggesting inhibition of the proteasome as a novel component of T2R14-induced apoptosis. Lidocaine may have therapeutic potential in HNSCC as a topical gel or intratumor injection, warranting future clinical studies. HIGHLIGHTSO_LILidocaine activates bitter taste receptor 14 (T2R14) to increase intracellular Ca2+ and decrease cAMP in head and neck squamous cell carcinoma (HSNCC) cells C_LIO_LILidocaine decreases cell viability and cell proliferation, depolarizes the mitochondrial membrane, and causes production of reactive oxygen species (ROS) C_LIO_LIT2R14 activation with lidocaine induces apoptosis and inhibits the ubiquitin proteasome system (UPS) C_LIO_LILung squamous cell carcinoma (SCC) cells and HNSCC tumor spheroids undergo apoptosis or structural disbandment, respectively, with lidocaine C_LI