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Potassium channel-driven bioelectric signaling affects the metastatic potential of triple negative breast cancer

ABSTRACT: Our data demonstrate that altering the RMP of triple-negative breast cancer (TNBC) cells by manipulating potassium channels increases in vitro invasion, tumor growth, and metastasis, inducing changes in gene expression associated with cell adhesion. We describe a novel mechanism for RMP-mediated cell migration involving cadherin-11 and the MAPK pathway. Importantly, we identify a new treatment strategy for metastatic TNBC by repurposing FDA-approved potassium channel blockers. Our results provide an understanding of a mechanism by which the bioelectricity regulates cancer cell invasion and metastasis that can advance the development of a potential new class of TNBC therapeutics.

ORGANISM(S): Homo sapiens

PROVIDER: GSE171150 | GEO | 2021/09/01

REPOSITORIES: GEO

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EAG2 potassium channel with evolutionarily conserved function as a brain tumor target

Project description:Characterizing the impact of pharmacological and shRNA-mediated silencing of EAG2 in medulloblastoma. Medulloblastoma (MB) is the most common pediatric CNS malignancy. Previously, we demonstrated that overexpression of the ion channel EAG2, identified in a subset of histological and molecular subtypes of this disease, functionally contributes to tumor progression (PMID: 22855790). Here, we demonstrate the evolutionarily conserved function of EAG2 potassium channel in promoting brain tumor growth and metastasis, delineate downstream pathways and uncover a co-option mechanism for different potassium channels to regulate mitotic cell volume and tumor progression. We show that EAG2 potassium channel is enriched at the trailing edge of migrating MB cells to regulate local cell volume dynamics, thereby facilitating cell motility. We identify the FDA- approved antipsychotic drug thioridazine as an EAG2 channel blocker that reduces xenografted MB growth and metastasis, and present a case report of repurposing thioridazine for treating a human patient. Our findings thus illustrate the potential of targeting ion channels in cancer treatment.

2015-07-08 | GSE70576 | GEO

Confirmation of recombinant Calcium-activated potassium channel from Leishmania donovani

Project description:Calcium-activated potassium channels are important membrane proteins that help in maintaining the cellular physiology and cell signalling. Till date no Calcium-activated potassium channels have been identified in Leishmania donovani. It’s gene was cloned into pET vector and expressed in E. coli BL21 (DE3). The recombinant protein was purified using nickel affinity chromatography.

2021-05-11 | PXD019577 | Pride

Protein Tyrosine Phosphatase UBASH3B is Overexpressed in Triple-Negative Breast Cancer and Promotes Invasion and Metastasis

Project description:Efforts to improve the clinical outcome of highly aggressive triplenegative breast cancer (TNBC) have been hindered by the lack of effective targeted therapies. Hence, it is important to identify the specific gene targets/pathways driving the invasive phenotype to develop more effective therapeutics. Here we show that UBASH3B (ubiquitin associated and SH3 domain containing B), a protein tyrosine phosphatase, is overexpressed in TNBC, where it supports malignant growth, invasion and metastasis in large through modulating EGFR. We also show that UBASH3B is a functional target of anti-invasive miR-200a that is downregulated in TNBC. Importantly, the oncogenic potential of UBASH3B is dependent on its tyrosine phosphatase activity, which targets CBL ubiquitin ligase for dephosphorylation and inactivation, leading to EGFR upregulation. Thus, UBASH3B may function as a crucial node in bridging multiple invasion-promoting pathways, thus providing a potential new therapeutic target for TNBC. Breast cancer tissues and breast cancer cell lines

2013-06-01 | E-GEOD-36693 | biostudies-arrayexpress

Satellite glial GPR37L1 and its ligand maresin 1 regulate potassium channel signaling and pain homeostasis.

Project description:G protein-coupled receptor 37-like 1 (GPR37L1) is an orphan GPCR, and its function remains largely unknown. Here we report that Gpr37l1 and GPR37L1 are among the most highly expressed GPCR transcripts in mouse and human dorsal root ganglia (DRGs) and are selectively expressed in satellite glial cells (SGCs). Peripheral neuropathy following PTX-induced pain resulted in a downregulation of GPR37L1 plasma membrane expression in DRGs. Transgenic mice with Gpr37l1 deficiency exhibited impaired resolution of neuropathic pain symptoms following PTX-induced pain, whereas overexpression of Gpr37l1 in mouse DRGs reversed pain. GPR37L1 regulates the surface expression and function of these potassium channels. Thus, GPR37L1 in SGCs offers a new target for neuropathy protection and pain control.

2024-03-06 | GSE260669 | GEO

Slo2 potassium channel function depends on a SCYL1 protein

Project description:Slo2 potassium channel function depends on a SCYL1 protein

| PRJNA593043 | ENA

N-methyl-D-aspartate receptors mediate activity-dependent down-regulation of potassium channel genes during the expression of homeostatic intrinsic plasticity

Project description:Using whole-cell patch clamp recording and unbiased gene expression profiling in rat dissociated hippocampal neurons cultured at high density, we demonstrate here that chronic activity blockade induced by the sodium channel blocker tetrodotoxin leads to a homeostatic increase in action potential firing and down-regulation of potassium channel genes. In addition, chronic activity blockade reduces total potassium current, as well as protein expression and current of voltage-gated Kv1 and Kv7 potassium channels, which are critical regulators of action potential firing. Importantly, inhibition of N-Methyl-D-Aspartate receptors alone mimics the effects of tetrodotoxin, including the elevation in firing frequency and reduction of potassium channel gene expression and current driven by activity blockade, whereas inhibition of L-type voltage-gated calcium channels has no effect.

2017-09-21 | GSE104052 | GEO

Potassium starvation induces autophagy in yeast

Project description:Autophagy is a conserved process that recycles cellular contents to promote survival. Although nitrogen starvation is the canonical inducer of autophagy, recent studies have revealed several other nutrients important to this process. In this study, we used a quantitative, high-throughput assay to identify potassium starvation as a new and potent inducer of autophagy. We found that potassium-dependent autophagy requires the core pathway kinases Atg1, Atg5, Vps34, as well as other components of Phosphatidylinositol 3-kinase Complex I. Transmission electron microscopy revealed abundant autophagosome formation in response to both stimuli. RNA sequencing indicated distinct transcriptional responses – nitrogen affects transport of ions such as copper while potassium targets the organization of other cellular components. Thus, nitrogen and potassium share the ability to influence metabolic supply and demand but do so in different ways. Both inputs promote catabolism through bulk autophagy, but inhibit cellular anabolism through distinct mechanisms.

2020-06-06 | GSE151898 | GEO

Slo2 potassium channel function depends on a SCYL1 protein

Project description:Slo2 potassium channels play important roles in neuronal function, and their mutations in humans cause epilepsies and profound cognitive defects. However, little is known how Slo2 function is regulated by other proteins. In a genetic screen for suppressors of a sluggish phenotype caused by a hyperactive C. elegans Slo2 (SLO-2), mutants of adr-1, a gene important to RNA editing, were isolated. SLO-2 current in motor neurons is substantially decreased in the mutants. However, slo-2 transcripts have no detectable RNA editing events and exhibit a similar expression level in wild type and adr-1 mutants. In contrast, mRNA level of scyl-1, which encodes an orthologue of mammalian SCYL1 (a pseudokinase), is greatly reduced in adr-1 mutants due to deficient RNA editing at a single adenosine in its 3’-UTR. SCYL-1 physically interacts with SLO-2 in neurons. Single-channel open probability of SLO-2 in neurons is reduced by ~50% in scyl-1 knockout whereas that of human Slo2.2/Slack is doubled by SCYL1 in a heterologous expression system. These results suggest that SCYL-1/SCYL1 is an evolutionarily conserved regulator of Slo2 channels.

2019-12-03 | GSE141316 | GEO

Induction of potassium channel regulator KCNE4 in the submandibular lymph nodes of a melanoma metastasis model

Project description:Induction of potassium channel regulator KCNE4 in the submandibular lymph nodes of a melanoma metastasis model

| PRJNA809338 | ENA

Transcriptional response of Saccharomyces cerevisiae to potassium starvation

Project description:In this study we investigated the transcriptional response of the yeast Saccharomyces cerevisiae to potassium starvation. To this end yeast cells were grown for 60 min in media without potassium or in media with a standard potassium concnetration (50 mM KCl). Using Serial Analysis of Gene Expression (SAGE)-tag sequencing the effect of potassium starvation on the transcriptome was determined.

2014-12-11 | GSE57093 | GEO

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