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

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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.

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Acknowledgements

This work was supported by the National Health and Medical Research Council of Australia (1079671) and Cancer Council Queensland (1042819). We are grateful to Sunil Lakhani and The Brisbane Breast Bank (The University of Queensland Centre for Clinical Research, Brisbane, Australia) for providing the MDA-MB-468 and BT-20 cell lines and RNA from 184A1, 184B5, MCF10A and Bre-80-hTERT cells for this study. GM is supported by the Mater Foundation. The Translational Research Institute is supported by a grant from the Australian Government. SYNJ was funded by the Ministry of Higher Education Malaysia Scholarship. ED is the recipient of a NBCF fellowship (ECR13-04).

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Correspondence to G R Monteith.

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GRM and SJR-T are associated with QUE-Oncology Inc.

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Peters, A., Jamaludin, S., Yapa, K. et al. Oncosis and apoptosis induction by activation of an overexpressed ion channel in breast cancer cells. Oncogene 36, 6490–6500 (2017) doi:10.1038/onc.2017.234

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