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 show 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. Furthermore, overexpression of the von Hippel-Lindau tumour suppressor gene (VHL) leads to decrease in K_Ca currents. 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 human melanoma 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. [J Physiol Sci. 2007;57 Suppl:S220]