Knockdown of the small conductance Ca(2+)‐activated K(+) channels is potently cytotoxic in breast cancer cell lines

BACKGROUND AND PURPOSE: Small conductance calcium‐activated potassium (K(Ca)2.x) channels have a widely accepted canonical function in regulating cellular excitability. In this study, we address a potential non‐canonical function of K(Ca)2.x channels in breast cancer cell survival, using in vitro models. EXPERIMENTAL APPROACH: The expression of all K(Ca)2.x channel isoforms was initially probed using RT‐PCR, Western blotting and microarray analysis in five widely studied breast cancer cell lines. In order to assess the effect of pharmacological blockade and siRNA‐mediated knockdown of K(Ca)2.x channels on these cell lines, we utilized MTS proliferation assays and also followed the corresponding expression of apoptotic markers. KEY RESULTS: All of the breast cancer cell lines, regardless of their lineage or endocrine responsiveness, were highly sensitive to K(Ca)2.x channel blockade. UCL1684 caused cytotoxicity, with LD(50) values in the low nanomolar range, in all cell lines. The role of K(Ca)2.x channels was confirmed using pharmacological inhibition and siRNA‐mediated knockdown. This reduced cell viability and also reduced expression of Bcl‐2 but increased expression of active caspase‐7 and caspase‐9. Complementary to these results, a variety of cell lines can be protected from apoptosis induced by staurosporine using the K(Ca)2.x channel activator CyPPA. CONCLUSIONS AND IMPLICATIONS: In addition to a well‐established role for K(Ca)2.x channels in migration, blockade of these channels was potently cytotoxic in breast cancer cell lines, pointing to modulation of K(Ca)2.x channels as a potential therapeutic approach to breast cancer.