Title: Altered purinergic receptor-Ca2+ signaling associated with hypoxia-induced epithelial-mesenchymal transition in breast cancer cells
Authors: Azimi, I
Beilby, H
Davis, FM
Marcial, DL
Kenny, PA
Thompson, EW
Roberts-Thomson, SJ
Monteith, GR
Issue Year: 2016
Series Mol. Oncol.:
Abstract Hypoxia is a feature of the microenvironment of many cancers and can trigger epithelialmesenchymal transition (EMT), a process by which cells acquire a more invasive phenotype with enriched survival. A remodeling of adenosine 5'-triphosphate (ATP)-induced Ca2+ 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 Ca2+ signaling in a model of hypoxia-induced EMT in MDA-MB-468 cells. Like EGF, hypoxia treatment (1% O-2) was also associated with a significant reduction in the sensitivity of MDA-MB-468 cells to ATP (EC50 of 0.5 mu M for normoxic cells versus EC50 of 5.8 mu M 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-MB468 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. (C) 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
URI: https://publications.svi.edu.au/publications/2048
Other Identifiers 10.1016/j.molonc.2015.09.006
Publication type Article