• KATP
• TRPM5
• connexins
• ion channels
• pannexins
• tumor microenvironment

• breast cancer
• calcium dynamics
• electrophysiological model
• gap junction
• ion channels
• membrane potential

• Microtubule dynamics
• Mitosis
• Osmotic stress
• Rigosertib
• WNK1

• WNK Lysine-Deficient Protein Kinase 1/metabolism
• WNK Lysine-Deficient Protein Kinase 1/genetics
• WNK Lysine-Deficient Protein Kinase 1/antagonists & inhibitors
• Humans
• Microtubules/drug effects
• Microtubules/metabolism
• Osmotic Pressure/drug effects
• Signal Transduction/drug effects
• Glycine/analogs & derivatives
• Glycine/pharmacology
• Drug Resistance, Neoplasm/genetics
• Drug Resistance, Neoplasm/drug effects
• Antineoplastic Agents/pharmacology
• Tubulin Modulators/pharmacology
• Cell Line, Tumor
• Mitosis/drug effects
• CRISPR-Cas Systems

• Cancer
• Cell biology
• Molecular biology

• R01 HL149993 NHLBI NIH HHS
• R01 NS111943 NINDS NIH HHS

• calcium channels
• chloride channels
• ion channels
• magnesium channels
• potassium channels
• pulmonary hypertension
• vascular remodeling
• zinc channels

• Cell function
• Ion channel
• Leukemia
• Therapy

• Apoptosis
• Colletotrichum fructicola
• Hypovirulence
• Mycovirus
• β subunit of voltage-gated potassium channel

• Colletotrichum/pathogenicity
• Fungal Viruses/genetics
• Apoptosis
• Virulence/genetics
• Gene Expression Regulation, Fungal
• Fungal Proteins/genetics
• Fungal Proteins/metabolism
• Nicotiana/microbiology
• Nicotiana/virology
• Plant Diseases/microbiology
• Plant Diseases/virology

• Convolutional neural networks
• Deep learning
• Membrane proteins
• Multiple windows scanning
• Pre-trained language model

• Ion Channels/metabolism
• Ion Channels/chemistry
• Neural Networks, Computer
• Deep Learning
• Ion Transport

• Breast cancer
• Glycolysis
• Intracellular sodium
• NaK ATPase
• Ouabain
• Warburg effect

• DP190100510 Australian Research Council
• EP/S022104/1 Engineering and Physical Sciences Research Council
• RE/18/2/34213 British Heart Foundation
• WT 203148/Z/16/Z Wellcome Trust and EPSRC
• Wellcome Trust

• A549 cell line
• calcium dynamics
• cancer
• electrophysiology
• in silico models

• cutaneous wound healing
• human neonatal dermal fibroblast
• large conductance Ca2+-activated K+ channel
• normal human epidermal keratinocyte

• Humans
• Animals
• Rats
• Swine
• Cell Movement
• Down-Regulation
• Fibroblasts
• Hydrolases
• Large-Conductance Calcium-Activated Potassium Channels
• Wound Healing

• #2021R1I1A3044128 National Research Foundation of Korea
• #RS-2023-00219399 National Research Foundation of Korea

• Ion channel blocker
• anti-cancer agent
• drug repurposing.
• hydroquinidine
• lung cancer

• Humans
• Carcinoma, Non-Small-Cell Lung/drug therapy
• Carcinoma, Non-Small-Cell Lung/pathology
• Carcinoma, Non-Small-Cell Lung/metabolism
• Carcinoma, Non-Small-Cell Lung/genetics
• Lung Neoplasms/drug therapy
• Lung Neoplasms/pathology
• Lung Neoplasms/metabolism
• Lung Neoplasms/genetics
• Cell Proliferation/drug effects
• Apoptosis/drug effects
• Antineoplastic Agents/pharmacology
• Quinidine/pharmacology
• A549 Cells
• Gene Expression Regulation, Neoplastic/drug effects
• Cell Movement/drug effects
• Cell Line, Tumor

• Biophysics
• Cancer
• Patterning
• Plasticity
• Regeneration

• Humans
• Neoplasms
• Signal Transduction
• Bioengineering
• Biophysics
• Cell Communication
• Tumor Microenvironment

• RGPIN-2021-03783 National Sciences and Engineering Research Council of Canada
• RGPIN-2022-03260 National Sciences and Engineering Research Council of Canada
• RGPIN-2022-04162 National Sciences and Engineering Research Council of Canada

• ion channels
• omics technologies
• physiology
• transporters
• transportome

• Humans
• Biomedical Research
• Homeostasis
• Membrane Potentials

• calcium
• ion channel
• transient receptor potential (TRP) channels
• tumor metastasis
• tumor proliferation

• Male
• Animals
• Transient Receptor Potential Channels/genetics
• Transient Receptor Potential Channels/metabolism
• Neoplasms/drug therapy
• Signal Transduction
• Cell Proliferation

• Cigarette smoke
• NNK
• NNN
• molecular docking
• molecular dynamics simulations
• nicotine

• AQP1
• AQP4
• Alzheimer’s disease
• Parkinson’s disease
• aquaporins
• brain tumorigenesis
• cellular physiology
• central nervous system
• fluid homeostasis
• glymphatic system
• neurodegenerative diseases
• neuromyelitis optica
• permeability assays
• stroke
• therapeutic interventions

• cell volume regulation
• cell volume sensor
• potassium channels
• quartz crystal microbalance

• Cell Size
• Potassium Channels

• Antiepileptic drugs
• Antiepileptic drugs for cancer
• Breast cancer
• Cancer treatment
• Drug repurposing

• Neoplasms/drug therapy
• Humans
• Anticonvulsants/therapeutic use
• Drug Resistance, Neoplasm
• Cell Proliferation/drug effects
• Signal Transduction
• Animals

• Monash University

• cytostatic
• efflux inhibitor
• ion channel
• overcoming multidrug resistance

• 22-24-00604. Russian Science Foundation

• Anti-carcinogenic agent
• HCT-8
• Hydroquinidine
• Ion-channel blocker
• MIA PaCa-2
• SK-HEP-1

While improvements in technology have improved our ability to treat many forms of cancer when diagnosed at an early stage of the disease, the ability to improve survival and quality of life for patients with late stage disease has been limited, largely due to the ability of cancer cells to evade destruction when treatments block preferred paths for survival. Here, we review the role that ions and ion channels play in normal cell function, the development of disease and their role in the life and death of a cell. It is hoped that viewing cancer from the perspective of altered ion channel expression and ion balance may provide a novel approach for developing more effective treatments for this devastating disease.

Life depends upon the ability of cells to evaluate and adapt to a constantly changing environment and to maintain internal stability to allow essential biochemical reactions to occur. Ions and ion channels play a crucial role in this process and are essential for survival. Alterations in the expression of the transmembrane proteins responsible for maintaining ion balance that occur as a result of mutations in the genetic code or in response to iatrogenically induced changes in the extracellular environment is a characteristic feature of oncogenesis and identifies cancer as one of a constellation of diseases known as channelopathies. The classification of cancer as a channelopathy provides a different perspective for viewing the disease. Potentially, it may expand opportunities for developing novel ways to affect or reverse the deleterious changes that underlie establishing and sustaining disease and developing tolerance to therapeutic attempts at treatment. The role of ions and ion channels and their interactions in the cell’s ability to maintain ionic balance, homeostasis, and survival are reviewed and possible approaches that mitigate gain or loss of ion channel function to contribute to new or enhance existing cancer therapies are discussed.

Hypoxia refers to a state of oxygen limitation, which mainly mediates pathological processes in the human body and participates in the regulation of normal physiological processes. In the hypoxic environment, the main regulator of human body homeostasis is the hypoxia-inducible factor family (HIF). HIF can regulate the expression of many hypoxia-induced genes and then participate in various physiological and pathological processes of the human body. Ion-transporting proteins are extremely important types of proteins. Ion-transporting proteins are distributed on cell membranes or organelles and strictly control the inflow or outflow of ions in cells or organelles. Changes in ions in cells are often closely related to extensive physiological and pathological processes in the human body. Numerous studies have confirmed that hypoxia and its regulatory factors can regulate the transcription and expression of ion-transporting protein-related genes. Under hypoxic stress, the regulation and interaction of ion-transporting proteins by hypoxia often leads to diseases of various human systems and even tumors. Using ion-transporting proteins and hypoxia as targets to explore the mechanism of digestive system diseases and targeted therapy is expected to become a new breakthrough point.

• National Natural Science Foundation of China

Aquaporins are proteins able to regulate the transfer of water and other small substances such as ions, glycerol, urea, and hydrogen peroxide across cellular membranes. AQPs provide for a huge variety of physiological phenomena; their alteration provokes several types of pathologies including cancer and hematological malignancies. Our review presents data revealing the possibility of employing aquaporins as biomarkers in patients with hematological malignancies and evaluates the possibility that interfering with the expression of aquaporins could represent an effective treatment for hematological malignancies.

Aquaporins are transmembrane molecules regulating the transfer of water and other compounds such as ions, glycerol, urea, and hydrogen peroxide. Their alteration has been reported in several conditions such as cancer. Tumor progression might be enhanced by aquaporins in modifying tumor angiogenesis, cell volume adaptation, proteases activity, cell–matrix adhesions, actin cytoskeleton, epithelial–mesenchymal transitions, and acting on several signaling pathways facilitating cancer progression. Close connections have also been identified between the aquaporins and hematological malignancies. However, it is difficult to identify a unique action exerted by aquaporins in different hemopathies, and each aquaporin has specific effects that vary according to the class of aquaporin examined and to the different neoplastic cells. However, the expression of aquaporins is altered in cell cultures and in patients with acute and chronic myeloid leukemia, in lymphoproliferative diseases and in multiple myeloma, and the different expression of aquaporins seems to be able to influence the efficacy of treatment and could have a prognostic significance, as greater expression of aquaporins is correlated to improved overall survival in leukemia patients. Finally, we assessed the possibility that modifying the aquaporin expression using aquaporin-targeting regulators, specific monoclonal antibodies, and even aquaporin gene transfer could represent an effective therapy of hematological malignancies.

Potassium (K⁺) channels are highly regulated membrane proteins that control the potassium ion flux and respond to different cellular stimuli. These ion channels are grouped into three major families, Kv (voltage-gated K⁺ channel), Kir (inwardly rectifying K⁺ channel) and K2P (two-pore K⁺ channels), according to the structure, to mediate the K⁺ currents. In cancer, alterations in K⁺ channel function can promote the acquisition of the so-called hallmarks of cancer – cell proliferation, resistance to apoptosis, metabolic changes, angiogenesis, and migratory capabilities – emerging as targets for the development of new therapeutic drugs. In this review, we focus our attention on the different K⁺ channels associated with the most relevant and prevalent cancer types. We summarize our knowledge about the potassium channels structure and function, their cancer dysregulated expression and discuss the K⁺ channels modulator and the strategies for designing new drugs.

• K+ channels
• K+ channels expression
• cancer
• potassium channel blockers

Transmembrane protein 16A (TMEM16A) forms a plasma membrane-localized Ca²⁺-activated Cl- channel. Its gene has been mapped to an area on chromosome 11q13, which is amplified in head and neck squamous cell carcinoma (HNSCC). In HNSCC, TMEM16A overexpression is associated with not only high tumor grade, metastasis, low survival, and poor prognosis, but also deterioration of clinical outcomes following platinum-based chemotherapy. Recent study revealed the interaction between TMEM16A and transforming growth factor-β (TGF-β) has an indirect crosstalk in clarifying the mechanism of TMEM16A-induced epithelial-mesenchymal transition. Moreover, human papillomavirus (HPV) infection can modulate TMEM16A expression along with epidermal growth factor receptor (EGFR), whose phosphorylation has been reported as a potential co-biomarker of HPV-positive cancers. Considering that EGFR forms a functional complex with TMEM16A and is a co-biomarker of HPV, there may be crosstalk between TMEM16A expression and HPV-induced HNSCC. EGFR activation can induce programmed death ligand 1 (PD-L1) synthesis via activation of the nuclear factor kappa B pathway and JAK/STAT3 pathway. Here, we describe an interplay among EGFR, PD-L1, and TMEM16A. Combination therapy using TMEM16A and PD-L1 inhibitors may improve the survival rate of HNSCC patients, especially those resistant to anti-EGFR inhibitor treatment. To the best of our knowledge, this is the first review to propose a biological validation that combines immune checkpoint inhibition with TMEM16A inhibition.

• Ca2+-activated Cl− channel
• EGFR
• HPV
• Head and neck squamous cell carcinoma
• Metastasis
• NF-kB
• PD-L1
• Proliferation
• STAT3
• TGF-β
• TMEM16A

Cancer is primarily a disease of dysregulation – both at the genetic level and at the tissue organization level. One way that tissue organization is dysregulated is by changes in the bioelectric regulation of cell signaling pathways. At the basis of bioelectricity lies the cellular membrane potential or V_mem, an intrinsic property associated with any cell. The bioelectric state of cancer cells is different from that of healthy cells, causing a disruption in the cellular signaling pathways. This disruption or dysregulation affects all three processes of carcinogenesis – initiation, promotion, and progression. Another mechanism that facilitates the homeostasis of cell signaling pathways is the production of extracellular vesicles (EVs) by cells. EVs also play a role in carcinogenesis by mediating cellular communication within the tumor microenvironment (TME). Furthermore, the production and release of EVs is altered in cancer. To this end, the change in cell electrical state and in EV production are responsible for the bioelectric dysregulation which occurs during cancer. This paper reviews the bioelectric dysregulation associated with carcinogenesis, including the TME and metastasis. We also look at the major ion channels associated with cancer and current technologies and tools used to detect and manipulate bioelectric properties of cells.

• National Science Foundation

• TRPM7
• brain tumor
• brain tumour
• drug development
• drug target
• gliomas
• ion channels

• Anti-cancer agents
• Drug repurposing
• Molecular docking
• Non-cancer
• hERG inhibitors

• DU145 cells
• Eag1 channels
• imipramine
• patch clamp
• prostate cancer

• Estrogen
• Estrogen receptor
• N2A cells
• TASK-1 channels

Cancer is an aging-associated disease and caused by genomic instability that is driven by the accumulation of mutations and epimutations in the aging process. Although Ca²⁺ signaling, reactive oxygen species (ROS) accumulation, DNA damage response (DDR) and senescence inflammation response (SIR) are processed during genomic instability, the underlying mechanism for the cause of genomic instability and cancer development is still poorly understood and needs to be investigated. Nociceptive transient receptor potential (TRP) channels, which firstly respond to environmental stimuli, such as microbes, chemicals or physical injuries, potentiate regulation of the aging process by Ca²⁺ signaling. In this review, the authors provide an explanation of the dual role of nociceptive TRP channels in regulating cancer progression, initiating cancer progression by aging-induced genomic instability, and promoting malignancy by epigenetic regulation. Thus, therapeutically targeting nociceptive TRP channels seems to be a novel strategy for treating cancers.

Hepatocellular carcinoma (HCC) is a leading cause of cancer‐related death worldwide. Its high metastasis rate is significantly correlated with poor patient prognosis. Elucidating the molecular mechanism underlying HCC metastasis is essential for HCC treatment. Owing to their high conductance, large‐conductance calcium‐activated potassium channels (BK channels) play a critical role in the control of membrane potential and have repeatedly been proposed as potential targets for cancer therapy. Emerging evidence suggests that BK channels are involved in the progression of cancer malignancies. The present study investigated the role of BK channels in mediating the hypoxia‐stimulated migration of HCC cells both in vitro and in vivo in the absence and presence of various BK channels modulators. We found that BK channels were functionally expressed on the membranes of the SMMC‐7721 and Huh7 HCC cell lines. Furthermore, blockage or activation of BK channels on the surface of HCC cells correspondingly inhibited or promoted HCC cell proliferation, migration and invasion in hypoxia conditions, with altered expression and distribution of cell‐cell adhesion molecule E‐cadherin and typical marker of mesenchymal cells, Vimentin, but not N‐cadherin. Hypoxia conditions did not alter BK channels expression but increased its open probability. Moreover, BK channels blocker IbTX significantly inhibited HCC cell remote colonization in HCC cell xenografted mice. In conclusion, the results of this study suggest that blocking BK channels offers an attractive strategy for treating HCC.

• BK channels
• hepatocellular carcinoma
• migration
• proliferation
• xenografted mice

• A549 Cells
• Adenocarcinoma of Lung/metabolism
• Adenocarcinoma of Lung/pathology
• Cell Cycle
• Cell Cycle Checkpoints
• Cell Proliferation
• Computational Biology
• Computer Simulation
• Humans
• Ion Channels/metabolism
• Ion Transport
• Lung Neoplasms/metabolism
• Lung Neoplasms/pathology
• Markov Chains
• Membrane Potentials
• Models, Biological
• Patch-Clamp Techniques

• P30 CA008748 NCI NIH HHS
• P50 CA217694 NCI NIH HHS
• ZK 17 Austrian Science Fund FWF
• FWF Zukunftskolleg

• Apoptosis
• Cell cycle progression
• Cell viability
• Clonogenic efficiency
• DNA damage
• Kv11.1
• Methyl methanesulfonate
• PARP1 gene expression
• hERG channel

• CRAC channels
• Orai1
• SK3-Orai1 interplay
• STIM1
• store-operated channel activation (SOCE), Ca2+-activated K+ channels (KCa2+), SK3

• P 30567 Austrian Science Fund FWF
• P 32851 Austrian Science Fund FWF

• aquaporins
• cell differentiation
• cell migration
• mesenchymal stem cells
• physiology
• water channel

• Aquaporins/chemistry
• Aquaporins/metabolism
• Biological Transport
• Brain/metabolism
• Cell Differentiation
• Cell Membrane Permeability/physiology
• Cell Movement
• Humans
• Mesenchymal Stem Cells/cytology
• Mesenchymal Stem Cells/metabolism
• Protein Isoforms/metabolism
• Regenerative Medicine

Gastric and colorectal cancers are the most common malignant tumours, leading to a significant number of cancer-related deaths worldwide. Recently, increasing evidence has demonstrated that cancer cells exhibit a differential expression of potassium channels and this can contribute to cancer progression. However, their expression and localisation at the somatic level remains uncertain. In this study, we have investigated the expression levels of KCNB1 and KCNA5 genes encoding ubiquitous Kv2.1 and Kv1.5 potassium channels in gastric and colorectal tumours.

Gastric and colorectal tumoral and peritumoral tissues were collected to evaluate the expression of KCNB1 and KCNA5 mRNA by quantitative PCR. Moreover, the immunohistochemical staining profile of Kv2.1 and Kv1.5 was assessed on 40 Formalin-Fixed and Paraffin-Embedded (FFPE) gastric carcinoma tissues. Differences in gene expression between tumoral and peritumoral tissues were compared statistically with the Mann-Whitney U test. The association between the clinicopathological features of the GC patients and the expression of both Kv proteins was investigated with χ2 and Fisher’s exact tests.

The mRNA fold expression of KCNB1 and KCNA5 genes showed a lower mean in the tumoral tissues (0.06 ± 0.17, 0.006 ± 0.009) compared to peritumoral tissues (0.08 ± 0.16, 0.16 ± 0.48, respectively) without reaching the significance rate (p = 0.861, p = 0.152, respectively). Interestingly, Kv2.1 and Kv1.5 immunostaining was detectable and characterised by a large distribution in peritumoral and tumoral epithelial cells. More interestingly, inflammatory cells were also stained. Surprisingly, Kv2.1 and Kv1.5 staining was undoubtedly and predominantly detected in the cytoplasm compartment of tumour cells. Indeed, the expression of Kv2.1 in tumour cells revealed a significant association with the early gastric cancer clinical stage (p = 0.026).

The data highlight, for the first time, the potential role of Kv1.5 and Kv2.1 in gastrointestinal-related cancers and suggests they may be promising prognostic markers for these tumours.

• Cancer diagnosis
• Colorectal cancer
• Gastric cancer
• Gene expression
• Intracellular localisation
• Kv1.5
• Kv2.1