Ca2+-activated K+ channels in human melanoma cells are up-regulated by hypoxia involving hypoxia-inducible factor-1alpha and the von Hippel-Lindau protein.

Under chronic hypoxia, tumour cells undergo adaptive changes involving hypoxia-inducible factors (HIFs). Here we report that ion currents mediated by Ca2+-activated K+ (K(Ca)) channels in human melanoma IGR1 cells are increased by chronic hypoxia (3% O2), as well as by hypoxia mimetics. This increase involves the HIF system as confirmed by overexpression of HIF-1alpha or the von Hippel-Lindau tumour suppressor gene. Under normoxic conditions the K(Ca) channels in IGR1 cells showed pharmacological characteristics of intermediate conductance K(Ca) subtype IK channels, whereas the subtype SK2 channels were up-regulated under hypoxia, shown with pharmacological tools and with mRNA analysis. Hypoxia increased cell proliferation, but the K(Ca) channel blockers apamin and charybdotoxin slowed down cell growth, particularly under hypoxic conditions. Similar results were obtained for the cell line IGR39 and for acutely isolated cells from a biopsy of a melanoma metastasis. Thus, up-regulation of K(Ca) channels may be a novel mechanism by which HIFs can contribute to the malignant phenotype of human tumour cells.