4851

Numerous studies have demonstrated that potassium channels interfere with pathways controlling the balance between cell growth and cell death. In contrast, the role of potassium channels in tumor cell dissemination and metastasis has been less intensively investigated. Potassium channels belong to the largest and the most diverse super-family of ions channels. One family of potassium channels, the calcium-activated potassium channels (KCa) comprises many channels which differ in their primary amino acid sequences and exhibit different single channel conductance and pharmacological profiles. Therefore, KCa channels can be divided into three subfamilies: big conductance (BKCa), intermediate conductance (IKCa) and small conductance (SKCa). Among KCa channels, apamin-sensitive small-conductance KCa (SKCa) comprise 3 subtypes, named SK1, SK2 and SK3, that are mainly expressed in the central nervous system. Little is known about the functional properties of SKCa channels in non-neuronal tissues. Particularly and most importantly, the expression and the role of the SKCa channels in mammary epithelial cells have never been explored. Since both intracellular Ca2+ and potassium channels have been involved in cell migration, we tested whether SKCa channels could be involved in this process. We report here that SKCa channels are expressed in a highly metastasizing mammary cancer cell line, MDA-MB-435s. Patch-clamp recordings demonstrated typical SKCa-mediated currents sensitive to apamin, 4-aminopyridine and tetraethylammonium. Moreover, the cells displayed a high intracellular calcium concentration, which was decreased after 24 h apamin treatment. By regulating membrane potential and intracellular calcium concentration, these channels were involved in MDA-MB-435s cell migration, but not in proliferation. Only SK3 protein expression was observed in these cells in contrast to SK2, which was expressed both in cancer and non-cancer cell lines. While siRNA directed against SK3 almost totally abolished MDA-MB-435s cell migration, transient expression of SK3 increased migration of the SK3-deficient cell lines, MCF-7 and 184A1. SK3 channel was solely expressed in tumor breast biopsies, and not in non-tumor breast tissues. In conclusion, the novel SK3 channel function presented here, taken together with the intrinsic SK3 channel expression in human breast cancer, suggest that the SK3 channel may become a potential target for a new class of anticancer agents.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA