Abstract
In the last decades, increasing evidence has revealed that a large number of channel protein and ion pumps exhibit impaired expression in cancers. This dysregulation is responsible for high proliferative rates as well as migration and invasiveness, reflected in the recently coined term oncochannelopathies. In glioblastoma (GBM), the most invasive and aggressive primary brain tumor, GBM cells modify their ionic equilibrium in order to change their volume as a necessary step prior to migration. This mechanism involves increased expression of BK channels and downregulation of the normally widespread Kir4.1 channels, as noted in GBM biopsies from patients. Despite a large body of work implicating BK channels in migration in response to an artificial intracellular calcium rise, little is known about how this channel acts in GBM cells at resting membrane potential (RMP), as compared to other channels that are constitutively open, such as Kir4.1. In this review we propose that a residual fraction of functionally active Kir4.1 channels mediates a small, but continuous, efflux of potassium at the more depolarized RMP of GBM cells. In addition, coinciding with transient membrane deformation and the intracellular rise in calcium concentration, brief activity of BK channels can induce massive and rapid cytosolic water loss that reduces cell volume (cell shrinkage), a necessary step for migration within the brain parenchyma.
Highlights
Glioblastoma (GBM, WHO grade IV astrocytoma) is the most common and malignant brain tumor (Brat et al, 2007; Furnari et al, 2007; Barbieri et al, 2018)
The intracellular calcium concentration and its spontaneous oscillations seem to be the main actor behind the scenes as it modulates a large fraction of the ion channels implicated in GBM invasion
Recent work has proposed that BK channels are modulated by mechanical stress on the membrane indicating that the dynamics of GBM cell membrane changes must be investigated
Summary
Glioblastoma (GBM, WHO grade IV astrocytoma) is the most common and malignant brain tumor (Brat et al, 2007; Furnari et al, 2007; Barbieri et al, 2018). In comparison to the majority of solid tumors, it is characterized by strong invasive and pro-angiogenic behavior associated with a poor prognosis with a median survival rate of about 15 months (Stupp et al, 2009). Because of the diffuse and aggressive invasiveness of GBM, it is generally not possible to achieve complete surgical resection, resulting in rapid relapse (Holland, 2001; Maher et al, 2001). GLIOBLASTOMA AS A CHANNELOPATHY: THE ROLE OF CHLORIDE AND POTASSIUM IONIC EQUILIBRIUM IN GBM CELL INVASIVENESS Death evasion minimizes the effect of all therapeutic strategies currently available, but enhanced invasiveness is the major feature that prevents successful treatment (Louis et al, 2007).
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