Department of Otorhinolaryngology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Pharmacology Graduate Group, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
Department of Otorhinolaryngology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
Cell Rep. 2023 Dec 26;42(12):113437. doi: 10.1016/j.celrep.2023.113437. Epub 2023 Nov 22.
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 Ca mobilization through activation of T2R14 in HNSCC cells. T2R14 activation with lidocaine depolarizes mitochondria, inhibits proliferation, and induces apoptosis. Concomitant with mitochondrial Ca 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.
头颈部鳞状细胞癌（HNSCC）死亡率高，与治疗相关的发病率高。发现有效、微创的治疗方法以提高生存率和生活质量至关重要。苦味受体（T2R）在 HNSCC 中表达，T2R 激活可诱导细胞凋亡。利多卡因是一种局部麻醉剂，也可激活苦味受体 14（T2R14）。利多卡因具有一定的抗癌作用，但机制尚不清楚。在这里，我们发现利多卡因通过激活 HNSCC 细胞中的 T2R14 引起细胞内 Ca 动员。利多卡因激活 T2R14 使线粒体去极化，抑制增殖并诱导细胞凋亡。伴随着线粒体 Ca 内流，ROS 产生导致 T2R14 依赖性多聚泛素化蛋白积累，表明蛋白酶体抑制有助于 T2R14 诱导的细胞凋亡。利多卡因作为局部凝胶或肿瘤内注射可能对头颈部鳞状细胞癌具有治疗潜力。此外，我们发现 HPV 相关（HPV+）的 HNSCC 与 TAS2R14 表达增加有关。利多卡因治疗可能使这些患者受益，值得进一步的临床研究。
