Activation Of Ca2+-Activated K+ Channel (Sk4) Rescues Squamous Cancer Cells From Iononmycin-Induced Cell Death

The ion channels in cancer cells are drawing attention regarding cell proliferation and migration. Intracellular Ca2+ ([Ca2+]i)-dependent signaling has crucial influence to the fate of cancer. Here we investigate the role of Ca2+-activated K+ channels in head and neck squamous carcinoma cells (HNSCC); SNU-1076, OSC-19 and HN5. Treatment with 1 μM ionomycin (24-48 h) induced cell death in all the three cell lines. Whole- cell patch clamp study revealed the functional expression of Ca2+-activated Cl- chan- nels (CaCC, Ano-1) and Ca2+-activated nonselective cation channels (CAN). Ca2+- activated K+ channel (SK4) activity was variable between cell lines; at a raised[Ca2+]i (0.6 μM) or with 1 μM ionomycin, only SNU-1076 showed prominent SK4 current (ISK4). However, an application of SK4 activator (1-EBIO) induced robust ISK4 with membrane hyperpolarization in OSC-19 as well as SNU-1076 while not in in HN5 cells. The EBIO-induced ISK4 was completely suppressed by TRAM-34, a selec-tive SK4 blocker. Interestingly, the ionomycin-induced cell death was effectively prevented by 1 - 30 μM 1-EBIO in SNU-1076 and OSC-19. Consistently, the rescue effect was annihilated by combined treatment with TRAM-34. The rescue by 1-EBIO was not effective in HN5. Above results newly demonstrate the role of SK4 and membrane hyperpolarization in HNSCCs' proliferation and death. Pharmacological modulation of SK4 might provide an intriguing novel tool for the anti-cancer strategy in HNSCC.