Targeting Ca2+-activated K+ channels in glioma

Abstract

Glioma affects millions of people worldwide and there is a lack of effective therapies. Glioblastoma multiforme (GBM) is the most common and deadliest form of primary brain tumor in adults. Emerging evidence indicated that targeting ion channels may be a promising therapeutic approach for GBM. Altered expression and activity of the Ca²⁺- activated K⁺ (K_Ca) channels have been reported in GBM patients. Generally, large-conductance K_Ca (BK_Ca) channels and intermediate-conductance K_Ca (IK_Ca or SK4) channels are highly expressed in glioma samples compared to healthy control brain tissue. Analyzing TCGA database, the expression of KCNMB1 (encoding the BK_Ca channel protein) and KCNN4 (encoding the K_Ca3.1/IK_Ca protein) genes was upregulated, while KCNN1 (encoding the K_Ca2.1 protein) gene expression was downregulated in GBM patients grade IV compared to GBM patients grade I or II. The gene expression and activity of K_Ca channels may contribute to survival outcomes, by regulating cellular processes like cell proliferation and migration. Importantly, modulation of the activity of K_Ca channels reduced the proliferation and migration of GBM cells and suppressed glioma progression both in vivo and in vitro cell models for GBM. Herein, we aim to review how modulation of the activity of K_Ca channels impacts tumor development in terms of proliferation, cell death, invasion, metabolism and immune system in GBM.