Potassium Ion Channels in Glioma: History
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Samar Younes
,
Nisreen Mourad
,
Mohamed Salla
,
Mohamad Rahal
,
Dalal Hammoudi Halat

Ion channels are transmembrane proteins that create a regulated pore structure through which ions can pass across the lipid bilayer of biological membranes. Ion channels, specifically those controlling the flux of potassium across cell membranes, have been shown to exhibit an important role in the pathophysiology of glioma, the most common primary central nervous system tumor with a poor prognosis.

  • potassium channels
  • glioma
  • proliferation
  • apoptosis
  • migration

1. Introduction to Ion Channels

In various aspects of life, the bioelectrical signals arising from the activity of ion channels are fundamental for different cellular processes and functions. Ion channels are transmembrane proteins that create a regulated pore structure through which ions can pass across the lipid bilayer of biological membranes [1][2]. When such an aqueous pore is open, ions move freely between cellular compartments, and this ion fluctuation can impact an armamentarium of pathways, including electrical excitation, signal transduction, regulation of secretion, and contractility, in addition to mechanisms that preserve normal tissue homeostases, such as cell proliferation, differentiation, migration, and apoptosis [3][4].
Despite spanning a different array of families, ion channels may be broadly categorized into voltage-gated channels and ligand-gated channels based on activation mechanisms and structural similarities, and such attributes and properties have been extensively reviewed [5][6][7]. With the transportation of ions having a critical role in cellular physiology, it is well known that the malfunction of ion channels can fundamentally lead to many diseases. In addition to signal transmission in nerves and muscle contraction, ion channels regulate brain activity, insulin secretion, water and ion transport, immune function, and others. Being ubiquitous and selective, they often require precise stereochemistry, with even subtle changes to their structures resulting in unfavorable physiological consequences [8]. With the wide distribution of channels and their remarkable roles, as well as the disorders associated with their structural or physiological malfunction, they have historically served as potential drug targets [9]. Not only have ion channel-targeting drugs been exploited in neuronal and cardiac diseases, but other nonclassical therapeutic benefits have emerged, including cystic fibrosis, smoking cessation, diabetes, and cancer [10]. Interestingly, lysosomal ion channels [11], mitochondrial ion channels [12], and Piezo channels [13] are also being prominently studied for their role in health and disease and represent a yet unraveled potential for a new era of therapeutics.

2. The Role of Ion Channels in Cancer

Voltage-sensitive ion channels have become a focus of research on cancer development into a more malignant phenotype. In cancer, various channels were found to be expressed in different cancer types, whereby they play major roles in cell proliferation, migration, invasion, and survival, as evidenced by the increased expression or increased kinetics of these channels upon malignant transformation [14]. As a result, these channels now represent promising directions for cancer therapy, whereby the blockade or reduction in their activity may be a strategy to prevent or treat oncological disorders [15]. Besides regulating several features of cancer cell behavior, ion channels are considered to be novel cancer biomarkers and show the potential to be exploited for diagnostic, prognostic, or predictive purposes [16]. With their location within the plasma membrane and the multiple layers of regulation they possess, ion channels represent key clinical targets for understanding cancer biology and for therapeutic intervention in many tumors, including gastrointestinal system cancers [17][18][19], as well as lung [20][21], prostate [22][23], breast [24][25], and central nervous system cancers [26][27][28].
Ion channels unquestionably play a vital role in several characteristics of cancer, and “oncochannelopathies” for calcium, sodium, and chloride ion channels have been described [3][29]. Moreover, it is well known that potassium channels are essential for cell proliferation [30][31], and potassium channel activity was increased in early investigations of viral infection leading to oncogenic changes [32]. Furthermore, a subunit of the large-conductance voltage and calcium-activated potassium channel (KCNMA1) revealed increased expression in the course of an extensive investigation of breast cancer tissue microarrays, an observation that may be related to the cancer’s high rate of proliferation and malignancy [33].
Potassium channels exist virtually in almost all species except some parasites and perform crucial roles. They are, by far, the largest, most diverse, and well-studied family of ion channels and include four subfamilies: voltage-gated K+ channels (Kv), Ca2+- and Na+-activated K+ channels (KCa, KNa), inwardly rectifying K+ channels (Kir), and two-pore domain K+ (K2P) channels [34]. These subfamilies differ by domain structure, gating mechanisms, and functions [35]. Potassium channels have been a major focus in oncology owing to their role in cell proliferation, differentiation, regulating cell volume, and maintaining membrane potential. The expression of an exhaustive array of potassium channels varies not only by cell type but also from normal to metastatic cells [36]. Several types of Kv channels are known to play a critical role during apoptosis due to their involvement in cell-cycle progression, resting membrane potential, and volume regulation, rendering them a potential molecular target in the diagnosis and therapy of some cancers [37]. Numerous studies have identified dysregulated potassium channel expression across many tumor types, including breast, prostate, lung, endometrium, pancreas, and others, and were extensively reviewed elsewhere [35]. In summary, the increased expression of potassium channels in cancer is associated with metastasis and tumorigenesis [38][39], higher-grade tumors [40][41], severe cancer phenotypes [42][43], cancer cell migration [44][45], proliferation through calcium regulation [46][47][48], and lower overall survival [49][50], among other effects. As such, the altered potassium ion channel expression serves central roles in neoplastic transformation and provides a toolkit that diverges from the healthy counterparts and warrants thorough investigation as a prevailing focus in cancer biology and therapeutics.

3. The Disease Burden of Glioma

As the most prevalent primary intracranial cancer, glioma represents over 80% of all brain tumors [51]. Although relatively rare, the incidence of glioma varies significantly by histologic type, age at diagnosis, gender, race, and country [51]. Generally, the overall age-adjusted incidence rate for all gliomas is about 6.0 per 100,000 population [52] or 250,000 new diagnoses per year worldwide [53]. According to data in 2022, glioma is more prevalent in older adults, with a peak incidence between 45 and 65 years of age. Nevertheless, gliomas are one of the most common solid tumors in children, accounting for over 45% of tumors among the age group of 0–19 years [54]. Gliomas derive their name from their originating cells, glial cells that support other cells of the brain, in contrast to nonglial tumors, that instigate from other brain structures, including nerves, blood vessels, and glands [55]. Based on the type of cell where they start, gliomas are further classified into astrocytomas, developed from star-shaped astrocytes that make up the larger part of the supportive brain tissue, oligodendrogliomas, originating from oligodendrocytes that produce the myelin sheath, and ependymomas, arising within the posterior fossa and supratentorial regions of the brain, as well as in the spinal cord. The median survival remains about 2–5 years for such gliomas [56][57]. On the other hand, glioblastoma multiforme (GBM) accounts for about 60–70% of all gliomas and is the most invasive and rapidly growing type of glial tumor. It originates from the anaplastic degeneration of different cells, including astrocytes, oligodendrocytes, and neural stem cells [58]. The most frequent malignant primary tumor of the central nervous system is GBM, with typical survival of 9 to 16 months, 2-year survival below 25%, and 5-year survival of 6.8% only, despite advancements in neurosurgery, radiation therapy, and chemotherapy. GBM is, therefore, regarded as one of the most fatal tumors, with a major problem in its treatment being the high resistance to chemotherapy and irradiation [59][60]. Despite tireless efforts over the past 20 years to create new treatment modalities for GMB, achieving long-term remissions in clinical trials is still remote, leaving only a few treatment options [61]. Studies show that GBM has a slight male predominance, with a male-to-female ratio of approximately 1.4:1 [62]. The clinical presentation of GBM can vary greatly depending on the stage and location of cancer, with symptoms including slow progressive neurologic deficits, usually motor weakness, in addition to commonly reported headache, nausea and vomiting, cognitive impairment, and seizure [63]. A significant burden is placed on the healthcare system, as well as on individual patients, for the treatment of this disease. Estimates of the median expenditure for an individual undergoing glioma treatment in 2019 was over $184,000, with radiation therapy accounting for the majority of this cost [64].
According to malignancy level, primary brain tumors are usually rated on a scale of I to IV, with increasing grade corresponding to higher malignancy. Gliomas are categorized as either low-grade (I and II) or high-grade (III and IV), whereas high-grade gliomas are also termed malignant or anaplastic gliomas. The latter is known for displaying high rates of mutations such as TP53, EGFR, or PTEN, which correlate with poor prognosis. All grade IV gliomas are glioblastomas [55]. Furthermore, the 2016 World Health Organization (WHO) classification of brain tumors classifies glioblastomas based on the mutational status of isocitrate dehydrogenase 1/2 (IDH). Most glioblastomas are IDH-wildtype (wt), which typically arise in patients aged over 50 years and are associated with poor prognosis. Only about 10% of glioblastomas are IDH-mutant (mut), which are often secondary tumors that arise from the progression of lower-grade gliomas and are associated with better survival compared to IDH-wt [65].
The major hindrance with malignant glioma remains its high migratory and invasive potential into the healthy brain parenchyma, avoiding the possibility of total surgical resection of tumor cells. Despite treatment, gliomas normally recur at or near the surgical site, establishing new tumors more resistant to further treatment, and are the primary cause of mortality. Questionably, at the time of surgery, a large number of cells have already detached from the original tumor and invaded far brain areas causing glioma metastasis [66]. Other typical features of malignant gliomas are their high proliferation rates, copious mitosis, and circumvention from apoptosis, probably due to common gene mutations that result in the dysregulation of the major growth factor signaling pathways [67].

4. Ion Channels in Glioma and the Importance of Potassium Channels

During oncogenic transformation, it is expected that genes encoding ion channels are affected [3]. For instance, upon microarray-assisted expression profiling of ion channel genes in breast cancer [68], lung adenocarcinoma [69][70], and glioma [71], a total of 30, 37, and 18 ion channel genes, respectively, were differentially expressed compared with normal tissues. As such, ion channel dysregulation may contribute to the pathophysiological features of different cancers, and data on their involvement in carcinogenesis, have been increasing exponentially [72]. In glioma, ion channels have been identified as promising therapeutic targets that may decrease the invasiveness of brain tumor cells [73]. Of the channels investigated, the transient receptor potential (TRP) channels and low threshold-activated calcium channels have similarly important roles in brain malignancy since dysregulated calcium ion signals profoundly affect glioma cell proliferation, migration, and invasion [74][75]. Furthermore, both chloride and potassium channels have emerged as vital gateways to facilitate cell volume changes [76] and participate in the blockade of apoptosis [77]. The movement of ions across these channels causes cytoplasmic water to move across the membrane, permitting robust shape and volume changes. Volume changes are necessary for tumor migration and, if inhibited, may block this process [78]. Calcium-activated potassium channels have a major role in such activity [79][80]. Moreover, altered expression of ion channels, especially potassium channels, conferred an invasive phenotype to GBM, and their modification significantly reduced tumor cell invasion both in vivo and ex vivo, according to the findings by Turner and Colleagues [81]. Glioma cells with a blockade of potassium channel functions through the drug temozolomide, a cytotoxic imidazotetrazine that forms O6-methylguanine, which mismatches with thymine during DNA replication, are sensitized to this drug, potentiating the antitumor effects [82]. Additionally, experiments performed on different glioma cell lines proved that novel potassium channel inhibitors induced massive cell death in vitro [59].
As such, it is evident that potassium ion channels play a hallmark role in brain cancer processes, including proliferation, invasion, migration, and angiogenesis, which are key drivers of tumor progression in glioma [35].

This entry is adapted from the peer-reviewed paper 10.3390/membranes13040434

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