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Western blot with samples from ovarian cancer tissue and SK-OV-3 cells demonstrating specific staining for Eag and HERG antibodies (Fig 1A and B) with corresponding actin blot.
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Ovarian cancer is the second most common cancer of the female genital tract in the United Kingdom (UK), accounting for 6% of female deaths due to cancer. This cancer is associated with poor survival and there is a need for new treatments in addition to existing chemotherapy to improve survival. Potassium (K+) channels have been shown to be overexpr...
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The human ether-a-go-go-related gene potassium channel (hERG, Kv11.1, KCNH2) has an essential role in cardiac action potential repolarization. Electrical dysfunction of the voltage-sensitive ion channel is associated with potentially lethal ventricular arrhythmias in humans. hERG K(+) channels are also expressed in a variety of cancer cells where t...
Citations
... Both molecules demonstrate significant functional implications in the oncogenesis of FTCs and thus may be employed as viable targets in patients with advanced FTC. In recent studies, it has been observed that ion channels of the plasma membrane play a significant role in various cancers (Pedersen and Stock, 2013) such as ovarian (Asher et al., 2010), prostate , and also thyroid tumor (Mato et al., 2015), (Gong et al., 2018). Reportedly, KCNN4 (Potassium Calcium-Activated Channel Subfamily N Member 4) is upregulated in the case of PTC (Wen et al., 2020), silencing of which restricts the proliferation, invasion, and migration in PTC cells. ...
Thyroid cancer's incidence has increased by leaps and bounds over the last years and accounts for 2.8% of new cases of cancers. This increasing bar is partially assisted by enormous screening to understand the sub-clinical status. Advanced tumor growth is the leading cause of thyroid cancer-associated death. However, the complete understanding of the underlying cause is still to be disclosed. The updated clinical assessment evidenced a few major oncogenes viz. RAS, BRAF, and RET as key drivers in the development and progression of thyroid cancer. The BRAF mutation, a major cause of aggressive tumor type in papillary thyroid carcinoma, is frequently reported. The characteristic oncogenic changes imply thyroid cancer to be clinically an ideal model for targeted therapy against RET, RAS, and BRAF mutation. Though the sensitive biochemical marker assay has been improvised, the diagnosis of thyroid follicular neoplasms is still a big challenge as the biopsy aspiration cannot define the nature of the tumor in 30% of the cases. The main hurdle is assisted distinction between follicular thyroid lesions. The discrimination between follicular thyroid adenomas and carcinomas is histologically accomplished. This strictly necessitates the identification of sensitive diagnostic/prognostic markers to mitigate the risk of thyroid cancer and to avoid the unnecessary hurdles of biopsy and surgery. An array of prognostic biomarkers is being used for the diagnosis of thyroid cancer. However, Estrogen Related Receptor Gamma (ERRγ) is setting a new benchmark among the clinical biomarkers. The dramatic expression of ERRγ in thyroid cancer enables itself not only to serve as a characteristic diagnostic marker but also as a therapeutic target. Recently, we have reported that ERRγ is upregulated in 96 papillary thyroid cancer (PTC) and 26 poorly differentiated/ anaplastic thyroid cancer (ATC) samples. Various synthetic ERRγ inverse agonists viz. GSK5182, DN200434, and 24e are fully proved to modulate ERRγ expression in ATC to attain partial cure. If this finding can be assayed on a larger scale the evaluation of this marker may be warranted and informative. This review article highlights the ascending sheds of clinical biomarkers of thyroid cancer. This also reveals the clinical importance of ERRγ as an evolving diagnostic and therapeutic target in thyroid cancer.
... Several studies reveal that ion channels regulate some tumoral cell processes, including high proliferation rate, invasiveness, and apoptosis (Prevarskaya et al., 2018). Specifically, the expression of voltage-gated potassium channels of the EAG (ether-à-go-go) subfamily has been related to promoting tumoral cell transformation, suggesting its oncogenic properties (Pardo et al., 1999;Asher et al., 2010). The restricted expression of Eag1 (Kv10.1) in healthy tissue and its overexpression in cancer cells identify Kv10.1 as tumoral markers with potential diagnostic, prognostic, and therapeutic application (Hemmerlein et al., 2006;Wang et al., 2017;Bauer and Schwarz, 2018). ...
... Experimental evidence in vivo has shown that pharmacological blockade of Kv10.1 channels with astemizole or imipramine reduces tumoral progression without induced regression by decreasing the cell proliferation rate (Gavrilova-Ruch et al., 2002;Downie et al., 2008). Although the use of channel inhibitors seems promising, their clinical usefulness is still limited by their side effects on other ion channels (Asher et al., 2010). ...
Exposure of biological systems to a radiation absorbed dose produces early and late radiogenic responses, such as ion channel modulation, oxidative stress, cell migration enhancement, and metabolic changes that could impact the efficiency of radiotherapy. To understand how radiation modulates ion channels, we irradiated HEK cells stably expressing the human ether à-go-go potassium channel-1 with gamma photons in the dose range of 2-10 Gy (60Co, 0.2 Gy/min) and measured ionic currents generated by the channel. The importance of the Kv10.1 modulation by gamma radiation was studied using cell proliferation. Results showed that a radiation-absorbed dose of 4 Gy significantly reduced the Kv10.1-evoked currents by depolarizing pulses between -100 mV and +50 mV. Additionally, the expression of Kv10.1 positively modulates HEK293 proliferation and, certainly, prevents the effect of gamma radiation on this phenomenon. Results allow concluding that the modulation of the functional expression of the Kv10.1 channel, induced by gamma radiation, leads to the expression of a radioresistant phenotype in Kv10.1 expressing cells.
... In contrast, ectopic expression of Kv10.1 is frequently detected in tumor biopsies ( Figure 1, Table 1) and cancer cell lines; several reports estimate that Kv10.1 is overexpressed in around 70% of clinical tumor samples [24,[41][42][43][44][45][46][47][48], where the Kv10.1 expression seems to confer some malignant or oncogenic properties, e.g., sustained proliferation. This effect has been corroborated by in-vitro and in-vivo pharmacological studies using non-selective Kv10.1-blockers or siRNA, both showing positive results (Table 2), i.e., reducing proliferation rate in cancer cell lines or xenograft tumor size in immunodeficient mice [24,31,32,[49][50][51][52]. ...
Carcinogenesis is a multistage process involving the dysregulation of multiple genes, proteins, and pathways that make any normal cell acquire a cancer cell phenotype. Therefore, it is no surprise that numerous ion channels could be involved in this process. Since their discovery and subsequent cloning, ion channels have been established as therapeutic targets in excitable cell pathologies (e.g., cardiac arrhythmias or epilepsy); however, their involvement in non-excitable cell pathologies is relatively recent. Among all ion channels, the voltage-gated potassium channels Kv10.1 have been established as a promising target in cancer treatment due to their high expression in tumoral tissues compared to low levels in healthy tissues.
... An analysis of Kv channel expression in human cancer cells [18] revealed an upregulation of Kv10.1 in a variety of tumors and can be found in blood, bone, brain, breast, stomach, colon, cervix cancer, and prostate cancers cells, thus providing a novel biomarker candidate and potential oncological target for cancer [5,19,20]. ...
... (subfamily H member 1, known as EAG1 or Ether-à-go-go 1), is implicated in various cellular processes, including, for example, cell proliferation [15]. An analysis of Kv channel expression in human cancer cells [18] revealed an up-regulation of Kv10.1 in a variety of tumors and can be found in blood, bone, brain, breast, stomach, colon, cervix cancer, and prostate cancers cells, thus providing a novel biomarker candidate and potential oncological target for cancer [5,19,20]. ...
The use of nanoelectromechanical systems or nanorobots offers a new concept for sensing and controlling subcellular structures, such as ion channels. We present here a novel method for mathematical modeling of ion channels based on control system theory and system identification. We investigated the use of nanoelectromechanical devices to control the activity of ion channels, particularly the activity of the voltage-gated ion channel Kv10.1, an important channel in cancer development and progression. A mathematical model of the dynamic behavior of the selected ion channel Kv10.1 in the Laplace (s) domain was developed, which is given in the representation of a transfer function. In addition, we addressed the possibilities of controlling ion channel activity by nanoelectromechanical devices and nanorobots and finally presented a control algorithm for the Kv10.1 as a control object. A use case demonstrates the potential of a Kv10.1 controlled nanorobot for cancer treatment at a single-cell level.
... In vitro and in vivo animal experiments showed that inhibiting the K V 10.1 channel leads to the reduction of tumour progression [7][8][9][10][11]. Therefore, inhibition of the K V 10.1 could increase the survival of patients with the fibrosarcoma [12], ovary carcinoma [13], glioblastoma [14], acute lymphoid leukaemia [15], gastric [16], head and neck [17] and colon cancers [18], all entities where a correlation between K V 10.1 and poorer outcome has been documented. Importantly, treatment with K V 10.1 inhibitors of brain metastasis patients improved survival in a retrospective study [14]. ...
Simple Summary
A novel structural class of inhibitors of the voltage-gated potassium channel KV10.1 was discovered by a ligand-based drug design method using a 3D pharmacophore model. The virtual screening hit compound ZVS-08 inhibited the channel in a voltage-dependent manner consistent with the action of a gating modifier. Structure–activity relationship studies revealed a nanomolar KV10.1 inhibitor that is selective for some KV and NaV channels but exhibits significant inhibition of the hERG channel. KV10.1 inhibitor 1 inhibited the growth of the MCF-7 cell line expressing high levels of KV10.1 and low levels of hERG more potently than the Panc1 cell line (no KV10.1 and high hERG expression). Moreover, the KV10.1 inhibitor 1 induced significant apoptosis in tumour spheroids of Colo-357 cells. This study may provide a basis for the use of computational drug design methods for the discovery of novel KV10.1 inhibitors as new promising anticancer drugs.
Abstract
(1) Background: The voltage-gated potassium channel KV10.1 (Eag1) is considered a near- universal tumour marker and represents a promising new target for the discovery of novel anticancer drugs. (2) Methods: We utilized the ligand-based drug discovery methodology using 3D pharmacophore modelling and medicinal chemistry approaches to prepare a novel structural class of KV10.1 inhibitors. Whole-cell patch clamp experiments were used to investigate potency, selectivity, kinetics and mode of inhibition. Anticancer activity was determined using 2D and 3D cell-based models. (3) Results: The virtual screening hit compound ZVS-08 discovered by 3D pharmacophore modelling exhibited an IC50 value of 3.70 µM against KV10.1 and inhibited the channel in a voltage-dependent manner consistent with the action of a gating modifier. Structural optimization resulted in the most potent KV10.1 inhibitor of the series with an IC50 value of 740 nM, which was potent on the MCF-7 cell line expressing high KV10.1 levels and low hERG levels, induced significant apoptosis in tumour spheroids of Colo-357 cells and was not mutagenic. (4) Conclusions: Computational ligand-based drug design methods can be successful in the discovery of new potent KV10.1 inhibitors. The main problem in the field of KV10.1 inhibitors remains selectivity against the hERG channel, which needs to be addressed in the future also with target-based drug design methods.
... Using a variety of K + channel inhibitors on the OC cell line A2780, Zhanping et al. demonstrated that Kv channels are the main K + channels affecting OC cell proliferation and cell cycle progression [110]. Among these, Kv10.1 (Eag) and Kv11.1 (hERG) are significantly upregulated in OC cell lines and tissue, contributing to the hyperpolarization of the cell membrane [111]. Such hyperpolarization may increase Ca 2+ influx into the cell through transport systems (ion channels and transporters) by increasing the driving force for Ca 2+ [112,113]. ...
Simple Summary
Around 4% of cancer deaths in the world was associated to ovarian cancer (OC), making it the eighth most common cause of death in women. Increasing evidence suggests that ion channels play critical role in the main stages of OC process, including proliferation, migration and metastasis. The aim of this review was to provide an updated description of the current knowledge concerning ion channels’ involvement in OC, with a particular emphasis of their role in the acquired chemoresistance. Importantly, ion channels might represent new molecular targets for the development of OC treatment, exploiting the availability of the well-known ion channel-targeting drugs.
Abstract
Ovarian cancer (OC) is the deadliest gynecologic cancer, due to late diagnosis, development of platinum resistance, and inadequate alternative therapy. It has been demonstrated that membrane ion channels play important roles in cancer processes, including cell proliferation, apoptosis, motility, and invasion. Here, we review the contribution of ion channels in the development and progression of OC, evaluating their potential in clinical management. Increased expression of voltage-gated and epithelial sodium channels has been detected in OC cells and tissues and shown to be involved in cancer proliferation and invasion. Potassium and calcium channels have been found to play a critical role in the control of cell cycle and in the resistance to apoptosis, promoting tumor growth and recurrence. Overexpression of chloride and transient receptor potential channels was found both in vitro and in vivo, supporting their contribution to OC. Furthermore, ion channels have been shown to influence the sensitivity of OC cells to neoplastic drugs, suggesting a critical role in chemotherapy resistance. The study of ion channels expression and function in OC can improve our understanding of pathophysiology and pave the way for identifying ion channels as potential targets for tumor diagnosis and treatment.
... Eag1 and the development of tumors for the first time in 1999 (20). Several studies have shown that an abnormal expression state of Eag1 in human tumor cell lines and tumor tissue can influence the proliferation, invasion, and other biological functions of tumor cells (21)(22)(23). This suggests that Eag1 may be a useful tumor biomarker for therapy in different cancers. ...
Background:
Heredity factors may play a vital role in gastric cancer (GC) progression. This study is aimed to explore and validate the influence and the role of Eag1 on the susceptibility to GC.
Methods:
The successfully constructed Ad5-Eag1-shRNA vector was transfected into GC cells [SGC-7901 and BGC-823, short hairpin RNA (shRNA) group]. Reverse transcription polymerase chain reaction (RT-PCR) and western blotting were conducted for assessment of Eag1 messenger RNA (mRNA) and protein expression levels. Cell proliferation and cell colony formation was measured by Cell Counting Kit-8 (CCK-8) assays. Flow cytometry was performed for cell cycle progression assessment. Bioinformatic analysis was analyzed for Eag1 validation with multiple public databases.
Results:
The expression of Eag1 was significantly down-regulated in the shRNA group in comparison with the empty vector and control groups (P<0.05). Cell proliferation rate and clone formation number were lower in the shRNA group, and a decreased cell proportion in G2-S phase and an increased proportion in G1-G0 were observed in the shRNA group (P<0.05). When transfected with Ad5-Eag1-shRNA, cyclin D1 and cyclin E protein expression were inhibited. Bioinformatic analysis showed that Eag1 expression was strongly associated with the prognosis and immune infiltration of GC.
Conclusions:
The Eag1 gene may affect occurrence and development of GC through regulating cyclin D1 and cyclin E expression.
... Over 70% of solid human tumors are Kv10.1-positive, which correlates with an unfavorable prognosis [5][6][7][8][9][10][11][12][13][14]. In contrast, inhibition of the channel reduces tumor cell proliferation both in vitro and in vivo, making Kv10.1 a promising target for cancer therapy [15][16][17][18][19][20]. ...
Kv10.1 (potassium voltage-gated channel subfamily H member 1, known as EAG1 or Ether-à-go-go 1), is a voltage-gated potassium channel, prevailingly expressed in the central nervous system. The aberrant expression of Kv10.1 is detected in over 70% of all human tumor tissues and correlates with poorer prognosis. In peripheral tissues, Kv10.1 is expressed almost exclusively during the G2/M phase of the cell cycle and regulates its progression—downregulation of Kv10.1 extends the duration of the G2/M phase both in cancer and healthy cells. Here, using biochemical and imaging techniques, such as live-cell measurements of microtubule growth and of cytosolic calcium, we elucidate the mechanisms of Kv10.1-mediated regulation at the G2/M phase. We show that Kv10.1 has a dual effect on mitotic microtubule dynamics. Through the functional interaction with ORAI1 (calcium release-activated calcium channel protein 1), it modulates cytosolic calcium oscillations, thereby changing microtubule behavior. The inhibition of either Kv10.1 or ORAI1 stabilizes the microtubules. In contrast, the knockdown of Kv10.1 increases the dynamicity of mitotic microtubules, resulting in a stronger spindle assembly checkpoint, greater mitotic spindle angle, and a decrease in lagging chromosomes. Understanding of Kv10.1-mediated modulation of the microtubule architecture will help to comprehend how cancer tissue benefits from the presence of Kv10.1, and thereby increase the efficacy and safety of Kv10.1-directed therapeutic strategies.
... The synergistic effects of BRAF V600E mutations and Telomerase Reverse Transcriptase promoter mutations are thought to generate more aggressive clinical characteristics Ion channels of the plasma membrane are known to be involved in various cancers [22]. For example, Potassium Voltage-Gated Channel Subfamily H Member 1 is associated with a poor prognosis in ovarian cancer [23], and Piezo Type Mechanosensitive Ion Channel Component 1 promotes prostate cancer proliferation by activating the Akt/Mammalian Target of Rapamycin pathway [24]. Regarding thyroid cancer, Voltage Dependent Anion Channel 2 improves the viability of PTC cell lines [25], whereas Sodium Voltage-Gated Channel Beta Subunit 4 is an independent indicator of enhanced recurrence-free survival in PTC patients [26]. ...
The incidence of thyroid cancer remains high worldwide, and papillary thyroid cancer (PTC) is the most common type. Potassium Calcium-Activated Channel Subfamily N Member 4 (KCNN4) has been reported as an oncogene in various cancers. We examined expression of KCNN4 in public databases and discovered that it is upregulated in PTC. We verified this finding using our own validated cohort and RNA sequencing data. We also found that KCNN4 is a diagnostic and prognostic biomarker that is associated with disease-free survival, immune infiltration, and several other clinicopathological features of PTC. Gene Set Enrichment Analysis indicated that apoptotic and epithelial-mesenchymal transition gene sets are both upregulated in PTC patients with higher KCNN4 levels. In PTC cell lines, silencing KCNN4 inhibited cell proliferation, migration and invasion. Moreover, quantitative real-time PCR and Western blotting indicated that silencing KCNN4 increased expression of apoptotic genes in PTC cells and reduced the expression of genes involved in their epithelial-mesenchymal transition. These results suggest that KCNN4 promotes PTC progression by inducing epithelial-mesenchymal transition and suppressing apoptosis, which suggests KCNN4 may be a useful diagnostic and prognostic biomarker of PTC.
... Some studies [111,112] described overexpressed levels of K + ether-à-go-go-1 channels (EAG1) and K + ether-à-go-go-1-related channels (ERG1) in GBMs. These observations are supported by other authors, who report increased ERG1 mRNA expression and high density of ERG1 channels even in other tumors [113], such as colorectal cancer [114], ovarian cancer [115], endometrial adenocarcinoma [116], and myeloid leukaemia [117]. These channels are physically linked to the signalling of β1-integrins, regulating many aspects of cell biology [118]. ...
The first description of epileptic seizures due to brain tumours occurred in 19th century. Nevertheless, after over one hundred years, scientific literature is still lacking on how epilepsy and its treatment can affect tumour burden, progression and clinical outcomes.
In patients with brain tumours, epilepsy dramatically impacts their quality of life (QoL). Even antiepileptic therapy seems to affect tumor lesion development. Numerous studies suggest that certain actors involved in epileptogenesis (inflammatory changes, glutamate and its ionotropic and metabotropic receptors, GABA-A and its GABA-AR receptor, as well as certain ligand- and voltage-gated ion channel) may also contribute to tumorigenesis. Although some antiepileptic drugs (AEDs) are known operating on such mechanisms underlying epilepsy and tumor development, few preclinical and clinical studies have tried to investigate them as targets of pharmacological tools acting to control both phenomena.
The primary aim of this review is to summarize known determinants and pathophysiological mechanisms of seizures, as well as of cell growth and spread, in patients with brain tumors. Therefore, a special focus will be provided on the anticancer effects of commonly prescribed AEDs (including levetiracetam, valproic acid, oxcarbazepine and others), with an overview of both preclinical and clinical data. Potential clinical applications of this finding are discussed.
