Oncosis and apoptosis induction by activation of an overexpressed ion channel in breast cancer cells

Peters, A. A., Jamaludin, S. Y. N., Yapa, K. T. D. S., Chalmers, S., Wiegmans, A. P., Lim, H. F., Milevskiy, M. J. G., Azimi, I., Davis, F. M., Northwood, K. S., Pera, E., Marcial, D. L., Dray, E., Waterhouse, N. J., Cabot, P. J., Gonda, T. J., Kenny, P. A., Brown, M. A., Khanna, K. K., Roberts-Thomson, S. J. and Monteith, G. R. (2017) Oncosis and apoptosis induction by activation of an overexpressed ion channel in breast cancer cells. Oncogene, 36 46: 6490-6500. doi:10.1038/onc.2017.234

Author Peters, A. A.
Jamaludin, S. Y. N.
Yapa, K. T. D. S.
Chalmers, S.
Wiegmans, A. P.
Lim, H. F.
Milevskiy, M. J. G.
Azimi, I.
Davis, F. M.
Northwood, K. S.
Pera, E.
Marcial, D. L.
Dray, E.
Waterhouse, N. J.
Cabot, P. J.
Gonda, T. J.
Kenny, P. A.
Brown, M. A.
Khanna, K. K.
Roberts-Thomson, S. J.
Monteith, G. R.
Title Oncosis and apoptosis induction by activation of an overexpressed ion channel in breast cancer cells
Journal name Oncogene   Check publisher's open access policy
ISSN 0950-9232
Publication date 2017-07-31
Year available 2017
Sub-type Article (original research)
DOI 10.1038/onc.2017.234
Open Access Status Not yet assessed
Volume 36
Issue 46
Start page 6490
End page 6500
Total pages 11
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Language eng
Subject 1312 Molecular Biology
1311 Genetics
1306 Cancer Research
Abstract The critical role of calcium signalling in processes related to cancer cell proliferation and invasion has seen a focus on pharmacological inhibition of overexpressed ion channels in specific cancer subtypes as a potential therapeutic approach. However, despite the critical role of calcium in cell death pathways, pharmacological activation of overexpressed ion channels has not been extensively evaluated in breast cancer. Here we define the overexpression of transient receptor potential vanilloid 4 (TRPV4) in a subgroup of breast cancers of the basal molecular subtype. We also report that pharmacological activation of TRPV4 with GSK1016790A reduced viability of two basal breast cancer cell lines with pronounced endogenous overexpression of TRPV4, MDA-MB-468 and HCC1569. Pharmacological activation of TRPV4 produced pronounced cell death through two mechanisms: apoptosis and oncosis in MDA-MB-468 cells. Apoptosis was associated with PARP-1 cleavage and oncosis was associated with a rapid decline in intracellular ATP levels, which was a consequence of, rather than the cause of, the intracellular ion increase. TRPV4 activation also resulted in reduced tumour growth in vivo. These studies define a novel therapeutic strategy for breast cancers that overexpress specific calcium permeable plasmalemmal ion channels with available selective pharmacological activators.
Keyword Neuronal Degeneration
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID 1079671
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Mater Research Institute-UQ (MRI-UQ)
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School of Chemistry and Molecular Biosciences
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Created: Fri, 20 Oct 2017, 12:46:25 EST by Gregory Monteith on behalf of School of Pharmacy