Quercetin as a Bitter Taste Receptor Agonist with Anticancer Effects in Head and Neck Cancer Cells

<b>Background/Objectives</b>: Quercetin is a bitter compound with demonstrated anticancer effects in preclinical models of head and neck squamous cell carcinoma (HNSCC). In taste transduction, bitter compounds activate bitter taste receptors (T2Rs), a group of G protein-coupled receptors with downstream signaling that includes cytosolic calcium (Ca²⁺) release. T2Rs are expressed in HNSCC cells, where their activation induces apoptosis in vitro. Increased T2R expression in HNSCC also correlates with improved patient survival. The objective of this study was to investigate the role of quercetin as an anticancer T2R agonist in HNSCC cells in vitro and ex vivo. <b>Methods</b>: Quercetin-mediated Ca²⁺ responses were assessed using live cell Ca²⁺ imaging in the presence of the T2R14 antagonist LF1 and G-protein inhibitor YM-254980 (YM) in UM-SCC-47 and FaDu HNSCC cell lines. Cell viability was evaluated using crystal violet assays in cell lines and MTS assays in patient-derived tumor slices. Mitochondrial depolarization was measured with TMRE in the presence and absence of T2R pathway inhibitors. <b>Results</b>: Quercetin induced a Ca²⁺ response in HNSCC cells, which was significantly reduced by LF1 and YM. Quercetin also decreased cell viability in vitro. Ex vivo experiments showed a decrease in viability that was not statistically significant. Finally, quercetin caused mitochondrial depolarization, which was reduced in the presence of LF1 but not by YM. <b>Conclusions</b>: In HNSCC cells, quercetin causes a Ca²⁺ response that is likely mediated by T2R14, although genetic knockdown or knockout models are needed to more definitively support this hypothesis. Additionally, quercetin decreases viability in vitro and causes mitochondrial depolarization.