Lidocaine induces apoptosis in head and neck squamous cell carcinoma through activation of bitter taste receptor T2R14

Cell Rep. 2023 Dec 26;42(12):113437. doi: 10.1016/j.celrep.2023.113437. Epub 2023 Nov 22.

Abstract

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.

Keywords: CP: Cancer; G-protein-coupled receptor; HPV+; anesthetic; apoptosis; bitter agonist; calcium; chemosensory receptor; cyclic-AMP; ubiquitin-proteasome system.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Head and Neck Neoplasms* / drug therapy
  • Humans
  • Lidocaine / pharmacology
  • Papillomavirus Infections*
  • Quality of Life
  • Receptors, G-Protein-Coupled / metabolism
  • Squamous Cell Carcinoma of Head and Neck
  • Taste / physiology

Substances

  • Receptors, G-Protein-Coupled
  • Lidocaine