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

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.

The Calcium-Signaling Toolkit in Cancer: Remodeling and Targeting

“…The process is effective in clinical trials (Falk et al 2018) and offers potentially less damage to normal surrounding tissue than coadministration with agents such as bleomycin, because many cancer types are more sensitive to Ca 2+ electroporation, perhaps because of compromised Ca 2+ efflux pathways (Frandsen et al 2017). An analogous phenomenon is seen with pharmacological Ca 2+ channel activators producing death in cancer cells that overexpress their Ca 2+ channel target (Zhang and Barritt 2004;Akbulut et al 2015;Peters et al 2017). The selective TRPV4 activator GSK1016790A induces cell death in MDA-MB-468 breast cancer cells overexpressing this Ca 2+permeable ion channel.…”

“…Although TRPV6 expression is associated with breast cancer hormone receptor expression, some members of the Ca 2+ signaling toolkit are linked to specific molecular subtypes, where cancers are classified by their expression of groups of genes. For TRPV4, expression is elevated in breast cancers of the basal molecular subtype compared with subtypes known as luminal A, luminal B, and HER2 breast cancers (Peters et al 2017). In the case of MDA-MB-468 basal breast cancer cells, the degree of TRPV4 overexpression is sufficient for the cell line to be highly sensitive to cell death initiated by the TRPV4 activator GSK1016790A (Peters et al 2017).…”

“…For TRPV4, expression is elevated in breast cancers of the basal molecular subtype compared with subtypes known as luminal A, luminal B, and HER2 breast cancers (Peters et al 2017). In the case of MDA-MB-468 basal breast cancer cells, the degree of TRPV4 overexpression is sufficient for the cell line to be highly sensitive to cell death initiated by the TRPV4 activator GSK1016790A (Peters et al 2017).…”

“…The selective TRPV4 activator GSK1016790A induces cell death in MDA-MB-468 breast cancer cells overexpressing this Ca 2+permeable ion channel. This death is via two mechanisms, oncosis and apoptosis (Peters et al 2017), with oncosis associated with close to maximal activation of TRPV4-mediated ion influx, and apoptosis associated with lower concentrations of GSK1016790A (Peters et al 2017). The association between excessive [Ca 2+ ] CYT accumulation and cell death is also seen following PMCA1 silencing in MDA-MB-231 breast cancer cells, where compromised Ca 2+ efflux results in greater sustained levels of global [Ca 2+ ] CYT and increased sensitivity to necrosis induced by the Ca 2+ ionophore ionomycin (Curry et al 2012).…”

“…Inhibition of TRPV4 expression reduces metastasis of breast cancer cells that have TRPV4 overexpression in vivo ). There may be some cases in which TRPV4 expression is so high that its pharmacological activation may promote cell death and suppress tumor growth (Peters et al 2017). Although the ideal target for the channelactivation approach would be one that does not contribute in any way to tumor progression (to avoid any risk of promotion of metastatic or proliferative pathways), appropriate dosing, patient selection, and combination therapies may allow for such an approach.…”