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

Yoona Seo; Yoo-Sun Kim; Kyung Eun Lee; Tai Hyun Park; Yuri Kim

doi:10.1371/journal.pone.0176851

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

PLoS One. 2017 May 3;12(5):e0176851. doi: 10.1371/journal.pone.0176851. eCollection 2017.

Authors

Yoona Seo¹, Yoo-Sun Kim¹, Kyung Eun Lee¹, Tai Hyun Park², Yuri Kim¹

Affiliations

¹ Department of Nutritional Science and Food Management, Ewha Womans University, Seoul, Republic of Korea.
² School of Chemical and Biological Engineering, Seoul National University, Seoul, Republic of Korea.

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.

MeSH terms

Animals
Cell Differentiation / physiology
Cell Line, Tumor
Gene Expression Regulation, Neoplastic / physiology
Glucose Transporter Type 1 / metabolism
Humans
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
Male
Mice
Mice, Inbred C57BL
Neoplasm Invasiveness
Neoplastic Stem Cells / metabolism*
Neoplastic Stem Cells / pathology
Neuroblastoma / metabolism*
Neuroblastoma / pathology
Receptors, Cell Surface / metabolism*
Receptors, G-Protein-Coupled / metabolism*
Taste Perception
Tretinoin / metabolism
Vascular Endothelial Growth Factor A / metabolism

Substances

Glucose Transporter Type 1
Hypoxia-Inducible Factor 1, alpha Subunit
Receptors, Cell Surface
Receptors, G-Protein-Coupled
TAS2R10 protein, human
TAS2R8 protein, human
Vascular Endothelial Growth Factor A
Tretinoin

Grants and funding

This work was supported by the Brain Korea 21 Plus (Project No. 22A20130012143). The funders had no roles in study design, data collection and analysis, decision to publish, or preparation of the manuscript.