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Chemosensory bitter taste receptors T2R4 and T2R14 activation attenuates proliferation and migration of breast cancer cells

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Abstract

The emerging significance of the bitter taste receptors (T2Rs) role in the extraoral tissues alludes to their potential role in many pathophysiological conditions. The dysregulation of T2R expression and function in disease conditions has now been demonstrated in airways diseases, neurological disorders, and in some cancers. However, the role of T2Rs in the pathophysiology of breast cancer is unexplored thus far. Previously, we demonstrated differential expression of the 25 T2Rs in breast cancer (BC) cells. Based on our previous findings we selected two T2Rs, T2R4 and T2R14 for this work. The objective of the current study is to investigate the expression of T2R4 and T2R14 in BC clinical samples and to examine their physiological role using highly metastatic BC and non-cancerous cell lines. Using approaches, which involve receptor knockdown, pharmacological activation and biochemical assays we report that (i) T2R4 and T2R14 expression patterns are dissimilar, with decreased levels of T2R4 and increased levels of T2R14 in BC clinical samples compared to non-cancerous controls. (ii) Activation of T2Rs with their respective agonist elicited physiological responses in metastatic breast cancer cells, and no responses were seen in non-tumorigenic breast epithelial cells. (iii) Agonist activation of T2Rs (irrespective of T2R subtype) induced anti-proliferative, pro-apoptotic, and anti-migratory responses in highly metastatic breast cancer cells. Taken together, our findings demonstrate that the chemosensory T2R signaling network is involved in evoking physiological responses in the metastatic breast cancer cell line.

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Abbreviations

API:

Apigenin

BC:

Breast cancer

FOXM1:

Forkhead box M1

GPCR:

G protein-coupled receptor

hEGF:

Human epidermal growth factor

PPARα1:

Peroxisome proliferator-activated receptor α1

QUI:

Quinine

qPCR:

Quantitative polymerase chain reaction

shRNA:

Short hairpin RNA

T2R:

Bitter taste receptor

TNBC:

Triple-negative breast cancer

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Acknowledgements

This work was supported by a grant from Natural Sciences and Engineering Research Council of Canada (RGPIN-2014-04099) to PC, a grant from Canadian Breast Cancer Foundation (CBCF) to YM and University of Manitoba Graduate Fellowships to FAS. We thank Anne Blanchard (Dept. of Pathology, University of Manitoba) for technical input. We also thank the Manitoba Breast Tumor Bank for providing the breast cancer patient samples and Dr. Aleksandra Glogowska (Dept. of Human Anatomy and Cell Science, University of Manitoba) for support with real-time migration assays.

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  1. Manitoba Chemosensory Biology Research Group, Department of Oral Biology, Rady Faculty of Health Sciences, Dr. Gerald Niznick College of Dentistry, Children’s Hospital Research Institute of Manitoba, University of Manitoba, D319, 780 Bannatyne Avenue, Winnipeg, MB, R3E 0W3, Canada

    Nisha Singh, Feroz Ahmed Shaik & Prashen Chelikani

  2. Department of Pathology, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB, Canada

    Yvonne Myal

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Singh, N., Shaik, F.A., Myal, Y. et al. Chemosensory bitter taste receptors T2R4 and T2R14 activation attenuates proliferation and migration of breast cancer cells. Mol Cell Biochem 465, 199–214 (2020). https://doi.org/10.1007/s11010-019-03679-5

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