• Adolescent
• Adult
• Child
• Child, Preschool
• Female
• Humans
• Infant
• Male
• Epilepsy/genetics
• Exome Sequencing
• Genetic Diseases, X-Linked/genetics
• Heterozygote
• Mutation, Missense/genetics
• Neurodevelopmental Disorders/genetics
• Pedigree
• Phenotype
• Shal Potassium Channels/genetics

• calcicoptosis
• cuproptosis
• drug resistance
• ferroptosis
• gastric cancer
• metal ion

• National Natural Science Foundation of China

• KCND2
• M2 macrophages
• NF-κB
• gastric cancer
• prognostic biomarker

• Animals
• Stomach Neoplasms/genetics
• Stomach Neoplasms/pathology
• Prognosis
• NF-kappa B
• Immunity
• Biomarkers

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

• Clinical targets
• Colorectal cancer
• Esophageal cancer
• Gastric cancer
• Gastrointestinal cancer
• Hepatocellular carcinoma
• Ion channels
• Novel therapies
• Pancreatic cancer
• Prognostic biomarker

• Animals
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Carcinogenesis/drug effects
• Carcinogenesis/pathology
• Disease Models, Animal
• Disease Progression
• Disease-Free Survival
• Down-Regulation
• Gastrointestinal Neoplasms/drug therapy
• Gastrointestinal Neoplasms/mortality
• Gastrointestinal Neoplasms/pathology
• Humans
• Ion Channels/antagonists & inhibitors
• Ion Channels/metabolism
• Up-Regulation

• R15 CA195061 NCI NIH HHS

• Auxiliary subunit
• Calcium channel
• Cancer
• Chloride channel
• Potassium channel
• Sodium channel

• Animals
• Biomarkers, Tumor/genetics
• Biomarkers, Tumor/metabolism
• Gene Expression Regulation, Neoplastic
• Humans
• Ion Channels/genetics
• Ion Channels/metabolism
• Neoplasms/metabolism
• Oncogenes/genetics
• Protein Subunits/genetics
• Protein Subunits/metabolism
• Signal Transduction
• Tumor Suppressor Proteins/genetics

• BB/M011151/1 Biotechnology and Biological Sciences Research Council

Voltage-gated potassium channels (Kv) are the largest group of ion channels. Kv are involved in controlling the resting potential and action potential duration in the heart and brain. Additionally, these proteins participate in cell cycle progression as well as in several other important features in mammalian cell physiology, such as activation, differentiation, apoptosis, and cell volume control. Therefore, Kv remarkably participate in the cell function by balancing responses. The implication of Kv in physiological and pathophysiological cell growth is the subject of study, as Kv are proposed as therapeutic targets for tumor regression. Though it is widely accepted that Kv channels control proliferation by allowing cell cycle progression, their role is controversial. Kv expression is altered in many cancers, and their participation, as well as their use as tumor markers, is worthy of effort. There is an ever-growing list of Kv that remodel during tumorigenesis. This review focuses on the actual knowledge of Kv channel expression and their relationship with neoplastic proliferation. In this work, we provide an update of what is currently known about these proteins, thereby paving the way for a more precise understanding of the participation of Kv during cancer development.

• K+ channels
• cancer
• cell cycle
• proliferation
• tumor progression

• KCND2
• overall survival
• recurrence-free survival
• gastric cancer

Gastric cancer (GC) is a common disease with few effective treatment choices and poor prognosis, and has the second-highest mortality rates among all cancers worldwide. Dysregulation and/or malfunction of ion channels or aquaporins (AQPs) are common in various human cancers. Furthermore, ion channels are involved in numerous important aspects of the tumor aggressive phonotype, such as proliferation, cell cycle, apoptosis, motility, migration, and invasion. Indeed, by localizing in the plasma membrane, ion channels or AQPs can sense and respond to extracellular environment changes; thus, they play a crucial role in cell signaling and cancer progression. These findings have expanded a new area of pharmaceutical exploration for various types of cancer, including GC. The involvement of multiple ion channels, such as voltage-gated potassium and sodium channels, intracellular chloride channels, ‘transient receptor potential’ channels, and AQPs, which have been shown to facilitate the pathogenesis of other tumors, also plays a role in GC. In this review, an overview of ion channel and aquaporin expression and function in carcinogenesis of GC is presented. Studies of ion channels or AQPs will advance our understanding of the molecular genesis of GC and may identify novel and effective targets for the clinical application of GC.

• Aquaporin
• Calcium
• Chloride
• Gastric cancer
• Ion channels
• Potassium
• Sodium
• Therapeutic target

Voltage-gated potassium (K_v) channels are known to be involved in cancer development and cancer cell proliferation. K_V9.3, an electronically silent subunit, forms heterotetramers with K_V2.1 in excitable cells and modulates its electrophysiological properties. However, the role of K_V9.3 alone in non-excitable cancer cells has not been studied. Here, we evaluated the effect of silencing K_V9.3 on cancer cell proliferation in HCT15 colon carcinoma cells and A549 lung adenocarcinoma cells. We confirmed the expression of K_V9.3 mRNA in HCT15 and A549 cells and showed that silencing K_V9.3 using small interfering RNA caused G0/G1 cell cycle arrest and alterations in cell cycle regulatory proteins in both HCT15 and A549 cells without affecting apoptosis. Also, stable knockdown of K_V9.3 expression using short-hairpin RNA inhibited tumor growth in SCID mouse xenograft model. Using a bioinformatics approach, we identified Sp1 binding sites in the promoter region of the gene encoding K_V9.3. We further found that Sp1 bound to this region and showed that the Sp1 inhibitor, mithramycin A, induced a concentration-dependent decrease in K_V9.3 expression. Taken together, these data suggest that knockdown of K_V9.3 inhibits proliferation in colon carcinoma and lung adenocarcinoma cell lines and may be regulated by Sp1.

• Kv9.3
• cancer
• colon
• lung
• proliferation

The KCNQ gene family, whose members encode Kv7 channels, belongs to the voltage-gated potassium (Kv) channel group. The roles of this gene family have been widely investigated in nerve and muscle cells. In the present study, we investigated several characteristics of Kv7.5, which is strongly expressed in the canine osteosarcoma cell line, CCL-183. Serum starvation upregulated Kv7.5 expression, and the Kv7 channel opener, flupirtine, attenuated cell proliferation by arresting cells in the G₀/G₁ phase. We also showed that Kv7.5 knockdown helps CCL-183 cells to proliferate. In an effort to find an endogenous regulator of Kv7.5, we used mithramycin A to reduce the level of the transcription factor Sp1, and it strongly inhibited the induction of Kv7.5 in CCL-183 cells. These results suggest that the activation of Kv7.5 by flupirtine may exert an anti-proliferative effect in canine osteosarcoma. Therefore, Kv7.5 is a possible molecular target for canine osteosarcoma therapy.

• Aminopyridines/pharmacology
• Animals
• Cell Line, Tumor
• Cell Proliferation/drug effects
• Culture Media, Serum-Free/pharmacology
• Dogs
• KCNQ Potassium Channels/agonists
• KCNQ Potassium Channels/genetics
• KCNQ Potassium Channels/metabolism
• Osteosarcoma/metabolism
• Plicamycin/analogs & derivatives
• Plicamycin/pharmacology
• Sp1 Transcription Factor/metabolism
• Transcription, Genetic/drug effects

Potassium channels have become a focus in cancer biology as they play roles in cell behaviours associated with cancer progression, including proliferation, migration and apoptosis. Two-pore domain (K_2P) potassium channels are background channels which enable the leak of potassium ions from cells. As these channels are open at rest they have a profound effect on cellular membrane potential and subsequently the electrical activity and behaviour of cells in which they are expressed. The K_2P family of channels has 15 mammalian members and already 4 members of this family (K_2P2.1, K_2P3.1, K_2P9.1, K_2P5.1) have been implicated in cancer. Here we examine the expression of all 15 members of the K_2P family of channels in a range of cancer types. This was achieved using the online cancer microarray database, Oncomine (www.oncomine.org). Each gene was examined across 20 cancer types, comparing mRNA expression in cancer to normal tissue. This analysis revealed all but 3 K_2P family members (K_2P4.1, K_2P16.1, K_2P18.1) show altered expression in cancer. Overexpression of K_2P channels was observed in a range of cancers including breast, leukaemia and lung while more cancers (brain, colorectal, gastrointestinal, kidney, lung, melanoma, oesophageal) showed underexpression of one or more channels. K_2P1.1, K_2P3.1, K_2P12.1, were overexpressed in a range of cancers. While K_2P1.1, K_2P3.1, K_2P5.1, K_2P6.1, K_2P7.1 and K_2P10.1 showed significant underexpression across the cancer types examined. This analysis supports the view that specific K_2P channels may play a role in cancer biology. Their altered expression together with their ability to impact the function of other ion channels and their sensitivity to environmental stimuli (pO2, pH, glucose, stretch) makes understanding the role these channels play in cancer of key importance.

• Databases, Genetic
• Gene Expression Regulation, Neoplastic
• Humans
• Neoplasms/genetics
• Neoplasms/metabolism
• Neoplasms/pathology
• Potassium/metabolism
• Potassium Channels, Tandem Pore Domain/genetics
• Potassium Channels, Tandem Pore Domain/metabolism

Many potassium ion (K⁺) channels function as oncogenes to sustain growth of solid tumors, but their role in cancer progression is not well understood. Emerging evidence suggests that the early progenitor cancer cell subpopulation, termed tumor initiating cells (TIC), are critical to cancer progression.

A non-selective antagonist of multiple types of K⁺ channels, tetraethylammonium (TEA), was found to suppress colony formation in endometrial cancer cells via inhibition of putative TIC. The data also indicated that withdrawal of TEA results in a significant enhancement of tumorigenesis. When the TIC-enriched subpopulation was isolated from the endometrial cancer cells, TEA was also found to inhibit growth in vitro.

These studies suggest that the activity of potassium channels significantly contributes to the progression of endometrial tumors, and the antagonists of potassium channels are candidate anti-cancer drugs to specifically target tumor initiating cells in endometrial cancer therapy.