Anti-cancer stemness and anti-invasive activity of bitter taste receptors, TAS2R8 and TAS2R10, in human neuroblastoma cells

Abstract

Neuroblastoma (NB) originates from immature neuronal cells and currently has a poor clinical outcome. NB cells possess cancer stem cells (CSCs) characteristics that facilitate the initiation of a tumor, as well as its metastasis. Human bitter taste receptors, referred to as TAS2Rs, are one of five types of basic taste receptors and they belong to a family of G-protein coupled receptors. The recent finding that taste receptors are expressed in non-gustatory tissues suggest that they mediate additional functions distinct from taste perception. While it is generally admitted that the recognition of bitter tastes may be associated with a self-defense system to prevent the ingestion of poisonous food compounds, this recognition may also serve as a disease-related function in the human body. In particular, the anti-cancer stemness and invasion effects of TAS2Rs on NB cells remain poorly understood. In the present study, endogenous expression of TAS2R8 and TAS2R10 in SK-N-BE(2)C and SH-SY5Y cells was examined. In addition, higher levels of TAS2R8 and TAS2R10 expression were investigated in more differentiated SY5Y cells. Both TAS2Rs were up-regulated following the induction of neuronal cell differentiation by retinoic acid. In addition, ectopic transfection of the two TAS2Rs induced neurite elongation in the BE(2)C cells, and down-regulated CSCs markers (including DLK1, CD133, Notch1, and Sox2), and suppressed self-renewal characteristics. In particular, TAS2RS inhibited tumorigenicity. Furthermore, when TAS2Rs was over-expressed, cell migration, cell invasion, and matrix metalloproteinases activity were inhibited. Expression levels of hypoxia-inducible factor-1α, a well-known regulator of tumor metastasis, as well as its downstream targets, vascular endothelial growth factor and glucose transporter-1, were also suppressed by TAS2Rs. Taken together, these novel findings suggest that TAS2Rs targets CSCs by suppressing cancer stemness characteristics and NB cell invasion, thereby highlighting the chemotherapeutic potential of bitter taste receptors.

Existing bitter medicines for fighting 2019‐nCoV‐associated infectious diseases

“…This suggests that TAS2R10 may be a key trigger of host defense pathways. Previous observations showing its anticancer activities and regulation of smooth muscle relaxation are consistent with our results 21,22 . Other studies showed that TAS2Rs can activate the robust calcium‐dependent secretion of antimicrobial peptides (AMPs), including β‐defensin 1 and 2, from epithelial cells in the respiratory tract 9,27,28 .…”

“…As such, it may largely contribute to the overall bitter tasting ability and exert broad effects on the human body. Despite several functional studies, 21,22 the detailed functions of TAS2R10 are not fully understood.…”

Systematic prediction of the biological functions of TAS2R10 using positive co‑expression analysis

“…It may be speculated that TAS2R10 is able to perform numerous biological functions. Recent studies have indicated other functions of TAS2R10 than bitterness-sensing (10). However, only two functions have been reported.…”

“…Furthermore, TAS2R10 was reported to mediate relaxation of vascular smooth muscles (9). Of note, TAS2R10 also has a tumor suppressor role in human neuroblastoma cells (10).…”

Cancer stem cells in neuroblastoma therapy resistance

“…Expressional deregulation of many other proteins are also causally linked to the dedifferentiation of nonstem cancer cells and formation of iCSCs [118,[145][146][147] . For instance, Lamin A/C, the type V intermediate filaments of nuclear lamina, is often reduced or absent in proliferative cells of various tumors [148,149] .…”