Dataset Information

Potassium Channels as a Target for Cancer Therapy: Current Perspectives.

ABSTRACT: 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.

SUBMITTER: Zuniga L

PROVIDER: S-EPMC9309325 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Potassium Channels as a Target for Cancer Therapy: Current Perspectives.

Zúñiga Leandro L Cayo Angel A González Wendy W Vilos Cristian C Zúñiga Rafael R

OncoTargets and therapy 20220720

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 t ...[more]

PMID: 35899081

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Project description:BackgroundCalcitriol (an active metabolite of vitamin D) modulates the expression of hundreds of human genes by activation of the vitamin D nuclear receptor (VDR). However, VDR-mediated transcriptional modulation does not fully explain various phenotypic effects of calcitriol. Recently a fast non-genomic response to vitamin D has been described, and it seems that mitochondria are one of the targets of calcitriol. These non-classical calcitriol targets open up a new area of research with potential clinical applications. The goal of our study was to ascertain whether calcitriol can modulate mitochondrial function through regulation of the potassium channels present in the inner mitochondrial membrane.MethodsThe effects of calcitriol on the potassium ion current were measured using the patch-clamp method modified for the inner mitochondrial membrane. Molecular docking experiments were conducted in the Autodock4 program. Additionally, changes in gene expression were investigated by qPCR, and transcription factor binding sites were analyzed in the CiiiDER program.ResultsFor the first time, our results indicate that calcitriol directly affects the activity of the mitochondrial large-conductance Ca2+-regulated potassium channel (mitoBKCa) from the human astrocytoma (U-87 MG) cell line but not the mitochondrial calcium-independent two-pore domain potassium channel (mitoTASK-3) from human keratinocytes (HaCaT). The open probability of the mitoBKCa channel in high calcium conditions decreased after calcitriol treatment and the opposite effect was observed in low calcium conditions. Moreover, using the AutoDock4 program we predicted the binding poses of calcitriol to the calcium-bound BKCa channel and identified amino acids interacting with the calcitriol molecule. Additionally, we found that calcitriol influences the expression of genes encoding potassium channels. Such a dual, genomic and non-genomic action explains the pleiotropic activity of calcitriol.ConclusionsCalcitriol can regulate the mitochondrial large-conductance calcium-regulated potassium channel. Our data open a new chapter in the study of non-genomic responses to vitamin D with potential implications for mitochondrial bioenergetics and cytoprotective mechanisms.

Dataset Information

Potassium Channels as a Target for Cancer Therapy: Current Perspectives.

Publications

Potassium Channels as a Target for Cancer Therapy: Current Perspectives.

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