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

Abstract

Head and Neck Squamous Cell Carcinomas (HNSCCs) have high mortality due to late stage diagnosis, high metastasis rates, and poor treatment options. Current therapies are invasive and aggressive, leading to a severe decline in patient quality of life (QoL). It is vital to create new therapies that are both potent and localized and/or targeted to prolong survival while maintaining QoL. Lidocaine is a local anesthetic used in HNSCC surgery settings. Lidocaine also activates bitter taste (taste family 2) receptor 14 (T2R14). T2Rs are G-protein coupled receptors (GPCRs) that increase intracellular Ca2+ when activated. T2Rs are expressed in mucosal epithelia, including internal regions of the head and neck, and are accessible drug targets. Here, we show that lidocaine increases intracellular Ca2+ and decreases cAMP in several HNSCC cell lines. Ca2+ release from the ER results in Ca2+ uptake into the mitochondria. Ca2+ mobilization is blocked with GPCR inhibitors and T2R14 antagonist, 6-methoxyflavanone. Lidocaine activation of T2R14 depolarizes the mitochondrial membrane, inhibits cell proliferation, and induces apoptosis. Lidocaine activates caspase-3 and -7 cleavage and also increases total caspase protein levels despite no changes in mRNA production. Both total and cleaved caspase products were upregulated even in the presence of cycloheximide, an inhibitor of protein synthesis. This suggests inhibition of the ubiquitin-proteasome system. It is vital to understand Lidocaine-induced apoptosis in HSNCCs to utilize its chemotherapeutic effects as a treatment option. In addition, future studies on T2R14 expression in HNSCC patients could provide insight for implementing lidocaine as a targeted topical therapy.

Salicin alleviates periodontitis via Tas2r143/gustducin signaling in fibroblasts

“…A typical bitter taste signal can lead to an increase in intracellular calcium (Ca 2+ ). This Ca 2+ reaction is usually elicited via gustducin/PLCb2 cascades, activation of voltage gated channel and transmitter release (13,17). Therefore, we investigated the activation of taste signaling by monitoring calcium mobilization.…”

Interkingdom Detection of Bacterial Quorum-Sensing Molecules by Mammalian Taste Receptors

“…One important aspect of T2R bitter receptors that makes them therapeutically attractive is the wide range of clinically-used compounds with existing safety data that are known to be bitter [ 135 , 137 , 277 ]. Such drugs may be repurposed to activate these receptors to stimulate defense antipathogen immune responses [ 278 , 279 ]. Moreover, many plant compounds are also bitter [ 179 , 280 , 281 , 282 , 283 , 284 ], and activation of T2Rs may explain particular beneficial effects with some homeopathic plant-based therapies.…”

Intracellular binding pocket revealed in the human bitter taste receptor TAS2R14

“…Polymorphisms in the TAS2R14 gene were associated with cardiac physiology (13) and male infertility (15). TAS2R14 overexpression was also documented in several types of cancer (12,16), and its stimulation was shown to elicit anti-proliferative and proapoptotic effects in multiple cancer cell lines (17)(18)(19). In addition, individuals diagnosed with pancreatic adenocarcinoma that have elevated TAS2R14 expression levels show an extended overall survival compared to those with lower expression of the receptor (19).…”