Denatonium as a Bitter Taste Receptor Agonist Modifies Transcriptomic Profile and Functions of Acute Myeloid Leukemia Cells

Abstract

The contribution of cell-extrinsic factors in Acute Myeloid Leukemia (AML) generation and persistence has gained interest. Bitter taste receptors (TAS2Rs) are G protein-coupled receptors known for their primary role as a central warning signal to induce aversion toward noxious or harmful substances. Nevertheless, the increasing amount of evidence about their extra-oral localization has suggested a wider function in sensing microenvironment, also in cancer settings. In this study, we found that AML cells express functional TAS2Rs. We also highlighted a significant association between the modulation of some TAS2Rs and the poor-prognosis AML groups, i.e., TP53- and TET2-mutated, supporting a potential role of TAS2Rs in AML cell biology. Gene expression profile analysis showed that TAS2R activation with the prototypical agonist, denatonium benzoate, significantly modulated a number of genes involved in relevant AML cellular processes. Functional assay substantiated molecular data and indicated that denatonium reduced AML cell proliferation by inducing cell cycle arrest in G0/G1 phase or induced apoptosis via caspase cascade activation. Moreover, denatonium exposure impaired AML cell motility and migratory capacity, and inhibited cellular respiration by decreasing glucose uptake and oxidative phosphorylation. In conclusion, our results in AML cells expand the observation of cancer TAS2R expression to the setting of hematological neoplasms and shed light on a role of TAS2Rs in the extrinsic regulation of leukemia cell functions.

An update on extra-oral bitter taste receptors

“…Salvestrini et al shed light on the role of TAS2Rs in the extrinsic regulation of leukaemic cell functions [ 255 ]. According to them, functional TAS2Rs coupled with the canonical signalling components, such as β-subunit of gustducin and PLC-β2, were detectable in primary leukemic cells of patients with acute myeloid leukaemia (AML) at diagnosis or in human leukaemia cell lines (OCI-AML3, THP-1) (Table 4 ).…”

“…This led to the hypothesis that upon DB exposure, non-proliferating AML cells show reduced cell motility and migration owing to their anchorage in the bone marrow niche, which may protect them from the effects of chemotherapy. It is also noteworthy that TAS2Rs and bitter intrinsic (such as amino acids [ 14 , 20 ]) or extrinsic (such as drugs [ 37 , 39 ]) molecules embedded in bone marrow niche might regulate leukaemia cell function; however, further research in this direction is warranted [ 255 ].…”

Denatonium Benzoate Exposure Promotes IgE-Mediated Mast Cell Degranulation and Allergy By Upregulating FcεRIα Expression

“…However, we found that such high levels of DB were cytotoxic and we were careful to exclude these effects in our experiments. Moreover, recent studies in the context of cancer showed that the viability of human myeloid leukemia primary leukemic cells and cell lines was reduced after exposure to DB concentrations exceeding 50 µM [30].This concentration was not cytotoxic in our studies, but the differences may possibly be reconciled from the different times of treatment. It is also possible that differences in T2Rs polymorphisms, cell lines differences ordrug preparations couldexplain these discrepancies.…”

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

“…Nuclear Ca 2+ regulates transcription factors but was also linked to apoptosis [53][54][55]. Bitter agonists activate apoptosis and/or mitochondrial depolarization in other cell types [56][57][58][59], including metastatic breast cancer [60], prostate cancer [61], and acute myeloid leukemia cells [59]. In pancreatic cancer, T2R38 can be activated by 3-oxo-C12HSL [15], suggesting a possible link with the microbiome.…”