BKCa channel inhibitor modulates the tumorigenic ability of hormone-independent breast cancer cells via the Wnt pathway

Abstract

In breast cancers, the large conductance Ca2+ and voltage sensitive K+ (BKCa) channels have been hypothesized to function as oncoproteins, yet it remains unclear how inhibition of channel activity impacts oncogenesis. We demonstrated herein that iberiotoxin (IbTX), an inhibitor of BKCa channels, differentially modulated the in vitro tumorigenic activities of hormone-independent breast cancer cells. Specifically, in HER-2/neu-overexpressing UACC893 cells and triple-negative MDA-MB-231 cells, IbTX selectively attenuated anchorage-independent growth with concomitant downregulation of β-catenin as well as total and phosphorylated Akt and HER-2/neu. By contrast, HER-2/neu-overexpressing SK-BR-3 cells were insensitive to IbTX. Molecular analyses showed an absence of β-catenin and a dose-dependent upregulation of total and phosphorylated Akt and HER-2/neu in these cells. Taken together, these studies identify β-catenin as a putative modulator of the inhibitory actions of IbTX in sensitive breast cancer cells.

BKCa participates in E2 inducing endometrial adenocarcinoma by activating MEK/ERK pathway

“…On the contrary, down-regulation of BKCa inhibited growth and metastasis of prostate cancer cells. BKCa was also hypothesized to function as oncoproteins in breast cancer [ 20 ], with metastatic breast cancer cells reported to exhibit increased BKCa activity, leading to greater invasiveness and migration [ 21 ]. Moreover, BKCa has been reported to act as a potential therapeutic target in breast cancer [ 22 ].…”

Evidence of BKCa Channelopathy-Driven Breast Cancer Metastasis to Brain

“…Altered ion channels could play a pivotal role in physiological angiogenesis in including cancer [30,31]. BK Ca channel inhibitor modulated the tumorigenic ability of hormone-independent breast cancer cells via the Wnt pathway [32]. Data shown are in SEM of n = 3 in triplicates.…”

“…This distinction would in turn allow for the appropriate and efficient application of effective diagnosis, prognosis and treatments while sparing patients with low risk for metastasis from the toxic side effects of chemotherapy. Activation of BK Ca channels was shown to be a novel molecular pathway involved in zoledronic acidinduced apoptosis of MDA-MB-231 cells in vitro [32]. Du et al [8] showed that BK Ca promotes growth and metastasis of prostate cancer through facilitating the coupling between αvβ3 integrin and FAK.…”

Alterations in Calcium Signaling Pathways in Breast Cancer

“…Large conductance Ca 2+ -activated K + channels (BKCa) were described to be expressed in several breast cancer cell lines (e.g., UACC893, SK-BR-3, and MDA-MB-231) [99]. Intermediateconductance, Ca 2+ -activated K + channels (hIK1) are also functionally expressed in MCF7 breast cancer cells, and their current density and basal cytosolic Ca 2+ concentration being augmented in cells synchronized at the end of the G1 or S phase with respect to the cells in the early G1 phase [100].…”

“…Iberiotoxin inhibits large conductance of Ca 2+ -activated K + channels (BKCa) in three types of breast cancer cell lines (e.g., UACC893, SK-BR-3, and MDA-MB-231), eliciting cellular depolarization, attenuating the anchorage-independent growth [99]. Oppositely, HER-2/neuoverexpressing SK-BR-3 cells were insensitive to iberiotoxin [99].…”