T2R bitter taste receptors regulate apoptosis and may be associated with survival in head and neck squamous cell carcinoma

Abstract

Better management of head and neck squamous cell carcinomas (HNSCCs) requires a clearer understanding of tumor biology and disease risk. Bitter taste receptors (T2Rs) have been studied in several cancers, including thyroid, salivary, and GI, but their role in HNSCC has not been explored. We found that HNSCC patient samples and cell lines expressed functional T2Rs on both the cell and nuclear membranes. Bitter compounds, including bacterial metabolites, activated T2R‐mediated nuclear Ca2+ responses leading to mitochondrial depolarization, caspase activation, and ultimately apoptosis. Buffering nuclear Ca2+ elevation blocked caspase activation. Furthermore, increased expression of T2Rs in HNSCCs from The Cancer Genome Atlas is associated with improved overall survival. This work suggests that T2Rs are potential biomarkers to predict outcomes and guide treatment selection, may be leveraged as therapeutic targets to stimulate tumor apoptosis, and may mediate tumor‐microbiome crosstalk in HNSCC.

The Role of Bitter Taste Receptors in Cancer: A Systematic Review

“…Moreover, more detailed sensory evaluations, not only including taste threshold levels, but also more detailed sensory descriptors, i.e., time intensity profiles of the bitterness perceived from individual compounds ingested with a complex food matrix, as well as quantitative analysis of the dietary intake would be meaningful to identify yet unknown relationships. Since TAS2Rs are not only present in taste cells, but also in extra-oral tissues [ 9 , 11 , 12 , 13 ], including cancer cells and tissues [ 17 , 18 , 19 , 20 , 21 , 22 , 24 , 25 , 26 ], the different genetic variants could also affect cancer-associated functions of TAS2Rs.…”

“…The functional response depends on the cell type which was activated, such as the gustatory sensation of bitter taste [ 9 ], a stimulated proton secretion of gastric parietal cells [ 14 ], a secretion of satiating hormones such as glucagon-like peptide from entero-endocrine cells [ 11 , 12 , 15 ], a decreased lipopolysaccharide-mediated interleukin 6 release from gingival fibroblasts [ 16 ], an intra-cellular mobilization of calcium leading to the release of nitric oxide and antimicrobial peptides in airway respiratory cells [ 12 , 13 ], and various effects on anti-cancer mechanisms [ 17 , 18 , 19 , 20 , 21 , 22 ]. The diverse biological functions mediated by TAS2R agonists suggest a potential use of bitter compounds in the prevention and treatment of various diseases [ 11 , 12 , 13 , 23 ], including various types of cancer [ 17 , 18 , 19 , 20 , 21 , 22 ]. TAS2Rs are also present and functionally active in cancerogenic cells [ 17 , 18 , 19 , 20 , 21 , 22 , 24 , 25 , 26 ].…”

“…The diverse biological functions mediated by TAS2R agonists suggest a potential use of bitter compounds in the prevention and treatment of various diseases [ 11 , 12 , 13 , 23 ], including various types of cancer [ 17 , 18 , 19 , 20 , 21 , 22 ]. TAS2Rs are also present and functionally active in cancerogenic cells [ 17 , 18 , 19 , 20 , 21 , 22 , 24 , 25 , 26 ]. In in vitro and in vivo experiments, bitter-tasting plant constituents [ 17 , 18 , 20 , 21 , 27 , 28 , 29 , 30 , 31 , 32 ] and extracts thereof [ 33 , 34 ] showed anti-cancer activities and/or synergistic effects with chemotherapeutic drugs.…”

“…TAS2Rs are also present and functionally active in cancerogenic cells [ 17 , 18 , 19 , 20 , 21 , 22 , 24 , 25 , 26 ]. In in vitro and in vivo experiments, bitter-tasting plant constituents [ 17 , 18 , 20 , 21 , 27 , 28 , 29 , 30 , 31 , 32 ] and extracts thereof [ 33 , 34 ] showed anti-cancer activities and/or synergistic effects with chemotherapeutic drugs. Various mechanisms for anti-cancer activities of bitter-tasting plant constituents, some of them involving TAS2Rs, have been demonstrated in these studies [ 17 , 18 , 20 , 21 , 27 , 29 , 30 , 31 , 32 , 33 , 34 ].…”

“…In in vitro and in vivo experiments, bitter-tasting plant constituents [ 17 , 18 , 20 , 21 , 27 , 28 , 29 , 30 , 31 , 32 ] and extracts thereof [ 33 , 34 ] showed anti-cancer activities and/or synergistic effects with chemotherapeutic drugs. Various mechanisms for anti-cancer activities of bitter-tasting plant constituents, some of them involving TAS2Rs, have been demonstrated in these studies [ 17 , 18 , 20 , 21 , 27 , 29 , 30 , 31 , 32 , 33 , 34 ]. However, the functional role of TAS2Rs in carcinogenesis and treatments thereof has not yet been elucidated and is hypothesized in this systematic review by summarizing evidence from the literature.…”