Lidocaine induces apoptosis in head and neck squamous cell carcinoma 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 T2R activation can induce apoptosis. Lidocaine is a local anesthetic that also activates bitter taste receptor 14 (T2R14). Lidocaine has some anti-cancer effects, but the mechanisms are unclear. Here, we find that lidocaine causes intracellular Ca2+ mobilization through activation of T2R14 in HNSCC cells. T2R14 activation with lidocaine depolarizes mitochondria, inhibits proliferation, and induces apoptosis. Concomitant with mitochondrial Ca2+ influx, ROS production causes T2R14-dependent accumulation of poly-ubiquitinated proteins, suggesting that proteasome inhibition contributes to T2R14-induced apoptosis. Lidocaine may have therapeutic potential in HNSCCs as a topical gel or intratumor injection. In addition, we find that HPV-associated (HPV+) HNSCCs are associated with increased TAS2R14 expression. Lidocaine treatment may benefit these patients, warranting future clinical studies. [Display omitted] •Lidocaine activates T2R14 to increase intracellular Ca2+ in HNSCC cells•Lidocaine decreases cell viability, depolarizes mitochondria, and leads to ROS•T2R14 activation with lidocaine induces apoptosis and inhibits the UPS via ROS•Lidocaine may be more effective in HPV+ HNSCCs with high TAS2R14 expression Miller et al. show that lidocaine activates bitter receptor T2R14 in head and neck squamous cell carcinoma (HNSCC) cells, causing apoptosis involving mitochondrial calcium and inhibition of the ubiquitin-proteasome system. T2R14 activation with lidocaine could be therapeutically leveraged for HNSCC, specifically in HPV+ cases associated with increased TAS2R14 expression.