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

Azimi, Iman, Beilby, Hannah, Davis, Felicity M., Marcial, Daneth L., Kenny, Paraic A., Thompson, Erik W., Roberts-Thomson, Sarah J., & Monteith, Gregory R. (2016) Altered purinergic receptor-Ca2+ signaling associated with hypoxia-induced epithelial-mesenchymal transition in breast cancer cells. Molecular Oncology, 10(1), pp. 166-178.

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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 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% 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. © 2015 Federation of European Biochemical Societies.

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ID Code: 97700
Item Type: Journal Article
Refereed: Yes
Keywords: Breast cancer, Calcium, Epithelial-mesenchymal transition, Hypoxia, Purinergic receptors, adenosine triphosphate, epidermal growth factor, messenger RNA, purinergic P2X receptor, purinergic P2X4 receptor, purinergic P2X5 receptor, purinergic P2X7 receptor, purinergic P2Y receptor, purinergic P2Y1 receptor, purinergic P2Y11 receptor, purinergic P2Y6 receptor, purinergic receptor, small interfering RNA, vimentin, Article, calcium signaling, cell hypoxia, cell migration, cell survival, controlled study, epithelial mesenchymal transition, gene expression profiling, gene silencing, genetic transcription, human, human cell, overall survival, phenotype, priority journal, protein expression, survival rate, tumor invasion, tumor microenvironment, upregulation
DOI: 10.1016/j.molonc.2015.09.006
ISSN: 1574-7891
Subjects: Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000)
Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > ONCOLOGY AND CARCINOGENESIS (111200)
Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > ONCOLOGY AND CARCINOGENESIS (111200) > Cancer Cell Biology (111201)
Divisions: Current > Schools > School of Biomedical Sciences
Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Owner: Copyright 2015 Federation of European Biochemical Societies
Deposited On: 31 Jul 2016 22:50
Last Modified: 01 Aug 2016 21:39

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