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

• DOI: 10.1038/onc.2017.234
• Publication Date: 2017-07-31T15:01:48Z
• Authors: A A Peters; S Y N Jamaludin; K T D S Yapa; S Chalmers; A P Wiegmans; H F Lim; M J G Milevskiy; I Azimi; F M Davis; K S Northwood; E Pera; D L Marcial; E Dray; N J Waterhouse; P J Cabot; T J Gonda; P A Kenny; M A Brown; K K Khanna; S J Roberts-Thomson; G R Monteith
• Keywords: 0301 basic medicine; Immunoblotting; Prostate-Cancer; 610; Mice, Nude; TRPV Cation Channels; Expression; Apoptosis; Breast Neoplasms; Neuronal Degeneration; Necrosis; 03 medical and health sciences; 1311 Genetics; Leucine; Cell Line, Tumor; 616; 1312 Molecular Biology; Homeostasis; Animals; Humans; 1306 Cancer Research; Consequences; Tumors; Mice, Inbred BALB C; Sulfonamides; Reverse Transcriptase Polymerase Chain Reaction; Molecular-Mechanisms; ion channels; cancer cell proliferation; Xenograft Model Antitumor Assays; 3. Good health; Death; Gene Expression Regulation, Neoplastic; Calcium; Female; RNA Interference; breast cancer cells

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.