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

Iman Azimi, Hannah Beilby, Felicity M. Davis, Daneth L. Marcial, Paraic A. Kenny, Erik W. Thompson, Sarah J. Roberts-Thomson, Gregory R. Monteith

Research output: Contribution to journalArticle

35 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)166-178
Number of pages13
JournalMolecular Oncology
Volume10
Issue number1
DOIs
StatePublished - Jan 1 2016
Externally publishedYes

Fingerprint

Purinergic Receptors
Epithelial-Mesenchymal Transition
Breast Neoplasms
Adenosine Triphosphate
Epidermal Growth Factor
Messenger RNA
Purinergic P2Y Receptors
Purinergic P2X Receptors
Up-Regulation
Phenotype
Hypoxia
Tumor Microenvironment
Vimentin
Small Interfering RNA
Intercellular Signaling Peptides and Proteins
Survival Rate
Pharmacology
Neoplasm Metastasis
Survival

Keywords

  • Breast cancer
  • Calcium
  • Epithelial-mesenchymal transition
  • Hypoxia
  • Purinergic receptors

ASJC Scopus subject areas

  • Cancer Research
  • Genetics
  • Molecular Medicine

Cite this

Azimi, I., Beilby, H., Davis, F. M., Marcial, D. L., Kenny, P. A., Thompson, E. W., ... Monteith, G. R. (2016). Altered purinergic receptor-Ca2+ signaling associated with hypoxia-induced epithelial-mesenchymal transition in breast cancer cells. Molecular Oncology, 10(1), 166-178. https://doi.org/10.1016/j.molonc.2015.09.006

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.

In: Molecular Oncology, Vol. 10, No. 1, 01.01.2016, p. 166-178.

Research output: Contribution to journalArticle

Azimi, I, Beilby, H, Davis, FM, Marcial, DL, Kenny, PA, Thompson, EW, Roberts-Thomson, SJ & Monteith, GR 2016, 'Altered purinergic receptor-Ca2+ signaling associated with hypoxia-induced epithelial-mesenchymal transition in breast cancer cells', Molecular Oncology, vol. 10, no. 1, pp. 166-178. https://doi.org/10.1016/j.molonc.2015.09.006
Azimi, Iman ; Beilby, Hannah ; Davis, Felicity M. ; Marcial, Daneth L. ; Kenny, Paraic A. ; Thompson, Erik W. ; Roberts-Thomson, Sarah J. ; Monteith, Gregory R. / Altered purinergic receptor-Ca2+ signaling associated with hypoxia-induced epithelial-mesenchymal transition in breast cancer cells. In: Molecular Oncology. 2016 ; Vol. 10, No. 1. pp. 166-178.
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