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Altered purinergic receptor-Ca2+ signaling associated with hypoxia-induced epithelial-mesenchymal transition in breast cancer cells

Citation

Azimi, I and Beilby, H and Davis, FM and Marcial, DL and Kenny, PA and Thompson, EW and Roberts-Thomson, SJ and Monteith, GR, Altered purinergic receptor-Ca2+ signaling associated with hypoxia-induced epithelial-mesenchymal transition in breast cancer cells, Molecular oncology, 10, (1) pp. 166-178. ISSN 1574-7891 (2016) [Refereed Article]

Copyright Statement

Copyright 2015 Federation of European Biochemical Societies

DOI: doi:10.1016/j.molonc.2015.09.006

Abstract

Hypoxia is a feature of the microenvironment of many cancers and can trigger epithelial-mesenchymal transition (EMT), a process by which cells acquire a more invasive phenotype with enriched survival. A remodeling of adenosine 5'-triphosphate (ATP)-induced Ca(2+) signaling via purinergic receptors is associated with epidermal growth factor (EGF)-induced EMT in MDA-MB-468 breast cancer cells. Here, we assessed ATP-mediated Ca(2+) signaling in a model of hypoxia-induced EMT in MDA-MB-468 cells. Like EGF, hypoxia treatment (1% O2) was also associated with a significant reduction in the sensitivity of MDA-MB-468 cells to ATP (EC50 of 0.5 μM for normoxic cells versus EC50 of 5.8 μM for hypoxic cells). Assessment of mRNA levels of a panel of P2X and P2Y purinergic receptors following hypoxia revealed a change in levels of a suite of purinergic receptors. P2X4, P2X5, P2X7, P2Y1 and P2Y11 mRNAs decreased with hypoxia, whereas P2Y6 mRNA increased. Up-regulation of P2Y6 was a common feature of both growth factor- and hypoxia-induced models of EMT. P2Y6 levels were also significantly increased in basal-like breast tumors compared to other subtypes and breast cancer patients with higher P2Y6 levels showed reduced overall survival rates. P2Y6 siRNA-mediated silencing and the P2Y6 pharmacological inhibitor MRS2578 reduced hypoxia-induced vimentin protein expression in MDA-MB-468 cells. P2Y6 inhibition also reduced the migration of mesenchymal-like MDA-MB-231 breast cancer cells. The up-regulation of P2Y6 appears to be a common feature of the mesenchymal phenotype of breast cancer cells and inhibition of this receptor may represent a novel therapeutic target in breast cancer metastasis.

Item Details

Item Type:Refereed Article
Keywords:Altered purinergic receptor‐Ca2+ signaling associated with hypoxia‐induced epithelial‐mesenchymal transition in breast cancer cells
Research Division:Medical and Health Sciences
Research Group:Oncology and Carcinogenesis
Research Field:Cancer Cell Biology
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Cancer and Related Disorders
Author:Azimi, I (Dr Iman Azimi)
ID Code:124408
Year Published:2016
Web of Science® Times Cited:25
Deposited By:Pharmacy
Deposited On:2018-02-21
Last Modified:2018-03-16
Downloads:0

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