Knockdown of the small conductance Ca2+‐activated K+ channels is potently cytotoxic in breast cancer cell lines

BACKGROUND AND PURPOSE Small conductance calcium-activated potassium (KCa2) channels have a widely accepted canonical function in regulating cellular excitability. In this study we address a potential non-canonical function of KCa2 channels in breast cancer cell survival using in vitro models. EXPERIMENTAL APPROACH The expression of all KCa2 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 KCa2 channels on these cell lines we utilized MTS proliferation assays and in conjunction followed the corresponding expression of apoptotic markers. KEY RESULTS All of the breast cancer cell lines, regardless of their lineage or endocrine responsiveness, were exquisitely sensitive to KCa2 channel blockade. UCL1684 caused cytotoxicity with an LD50 in the low nanomolar range in all cell lines. The role of KCa2 was confirmed using pharmacological inhibition and siRNA-mediated knockdown, this not only caused a reduction in cell viability, but also a reduced expression of Bcl-2 and increased expression of active caspase-7 and 9. Complementary to these results we also show a variety of cell lines can be protected from the effects of the apoptosis inducer staurosporine using the KCa2 channel activator CyPPA. CONCLUSIONS AND IMPLICATIONS These data clearly illustrate that in addition to a well-established role for KCa2 in migration, KCa2 channel blockade is potently cytotoxic in breast cancer cell lines and points to KCa2 channel modulation as a potential therapeutic avenue in breast cancer.