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

Abstract

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-1α 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.