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

Valentina Salvestrini, Marilena Ciciarello, Valentina Pensato, Giorgia Simonetti, Maria Antonella Laginestra, Samantha Bruno, Martina Pazzaglia, Elena De Marchi, Dorian Forte, Stefania Orecchioni, Giovanni Martinelli, Francesco Bertolini, Simon Méndez-Ferrer, Elena Adinolfi, Francesco Di Virgilio, Michele Cavo, Antonio Curti

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number1225
JournalFrontiers in Oncology
Volume10
DOIs
Publication statusPublished - Jul 24 2020

Keywords

  • acute myeloid leukemia
  • bitter compounds
  • bitter taste receptors
  • bone marrow microenvironment
  • denatonium benzoate

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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