Ion Channels and Their Role in the Pathophysiology of Gliomas

Abstract

Malignant gliomas are the most common primary central nervous system tumors and their prognosis is very poor. In recent years, ion channels have been demonstrated to play important roles in tumor pathophysiology such as regulation of gene expression, cell migration, and cell proliferation. In this review, we summarize the current knowledge on the role of ion channels on the development and progression of gliomas. Cell volume changes through the regulation of ion flux, accompanied by water flux, are essential for migration and invasion. Signaling pathways affected by ion channel activity play roles in cell survival and cell proliferation. Moreover, ion channels are involved in glioma-related seizures, sensitivity to chemotherapy, and tumor metabolism. Ion channels are potential targets for the treatment of these lethal tumors. Despite our increased understanding of the contributions of ion channels to glioma biology, this field remains poorly studied. This review summarizes the current literature on this important topic.

Figure 1.

Cell volume changing model during cell migration. Cell migration is thought to be modeled as a continuous cycle of protrusion of the migrating cell front and retraction of the trailing end. A) In the migrating edge, ion channels and transporters, such as NKCC1, cause ion influx leading to an osmotic gradient, which results in water flowing into the cell. B) TRP channels allow the influx of Ca²⁺, which activates ion channels in the trailing edge. TRPM7 and swelling-induced Cl⁻ channels are also thought to activate signaling pathways, such as MAPK/ERK signaling and PI3K/Akt pathways, leading to alterations in gene expression which enhance glioma cell migration and invasion. C) In the rear-end of the cell body, activated ion channels, such as CLC-3 and KCa3.1, induce ion and water efflux that causes cell shrinking only in the trailing end and results in cell retraction.

Figure 2.

Representative contributions of ion channels to glioma cell proliferation. TRPM7 may activate proliferation through the Notch, PI3K/mTOR, and MAPK pathways. The nuclear localization sequence (NLS) on hEAG/hERG causes perinuclear localization of these channels and activates the MAPK pathway. Increased hEAG/hERG expression and VGCC activity results in an increased influx of Ca²⁺ ions which causes increased cell cycle transition and cell proliferation through calmodulin activation. ANO1 overexpression activates NF-κB. Interestingly, Kv2.1 overexpression increases autophagy through phosphorylated ERK1/2, which results in increased apoptosis and attenuates proliferation. *; Postulated mechanism.