Potassium channel-driven bioelectric signaling affects the metastatic potential of triple negative breast cancer
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PROVIDER: PRJNA718555 | ENA |
REPOSITORIES: ENA
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Project description: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.
2021-09-01 | GSE171150 | GEO
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
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
Project description:Slo2 potassium channel function depends on a SCYL1 protein
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Project description:Sequencing cancer genomes is predicted to uncover therapeutic tumor vulnerabilities. This has been complicated by the abundance of genetic alterations which are either non-functional, or only important in tumor initiation or progression. Distinguishing tumor maintenance genes from initiation, progression, and passenger genes is critical for developing effective cancer therapy. We employed a functional genomic approach using the Lazy Piggy transposon to identify tumor maintenance genes in vivo, and apply this to SHH medulloblastoma (MB). Combining Lazy Piggy screening in mice and transcriptomic profiling of human MB, we discovered candidate maintenance genes including the voltage-gated potassium channel Kcnb2. Genetic knockout of Kcnb2 impairs MB growth. Kcnb2 mediates potassium efflux in MB-propagating cells to govern cell volume. Loss of Kcnb2 leads to chronic osmotic swelling and decreased plasma membrane tension, which elevates endocytosis to dampen Egfr signaling, thereby mitigating proliferation of MB-propagating cells. Kcnb2 is largely dispensable for mouse development and synergizes with anti-SHH therapy in treating MB. These results demonstrate the utility of the Lazy Piggy functional genomic approach in identifying cancer maintenance genes, and elucidate a mechanism by which a potassium channel integrates biomechanical and biochemical signaling to promote MB aggression.
2024-09-16 | GSE277171 | GEO
Project description:Sequencing cancer genomes is predicted to uncover therapeutic tumor vulnerabilities. This has been complicated by the abundance of genetic alterations which are either non-functional, or only important in tumor initiation or progression. Distinguishing tumor maintenance genes from initiation, progression, and passenger genes is critical for developing effective cancer therapy. We employed a functional genomic approach using the Lazy Piggy transposon to identify tumor maintenance genes in vivo, and apply this to SHH medulloblastoma (MB). Combining Lazy Piggy screening in mice and transcriptomic profiling of human MB, we discovered candidate maintenance genes including the voltage-gated potassium channel Kcnb2. Genetic knockout of Kcnb2 impairs MB growth. Kcnb2 mediates potassium efflux in MB-propagating cells to govern cell volume. Loss of Kcnb2 leads to chronic osmotic swelling and decreased plasma membrane tension, which elevates endocytosis to dampen Egfr signaling, thereby mitigating proliferation of MB-propagating cells. Kcnb2 is largely dispensable for mouse development and synergizes with anti-SHH therapy in treating MB. These results demonstrate the utility of the Lazy Piggy functional genomic approach in identifying cancer maintenance genes, and elucidate a mechanism by which a potassium channel integrates biomechanical and biochemical signaling to promote MB aggression.
2024-09-16 | GSE277172 | GEO
Project description:Microglia are resident immune cells of the brain and regulate its inflammatory state. In neurodegenerative diseases, microglia transition from a homeostatic state to a state referred to as disease associated microglia (DAM). DAM express higher levels of proinflammatory signaling molecules, like STAT1 and TLR2, and show transitions in mitochondrial activity toward a more glycolytic response. Inhibition of Kv1.3 decreases the proinflammatory signature of DAM, though how Kv1.3 influences the response is unknown. Our goal was to establish the potential proteins interacting with Kv1.3 during transition to DAM. We utilized TurboID, a biotin ligase, fused to Kv1.3 to evaluate the potential interacting proteins with Kv1.3 via mass spectrometry in BV-2 microglia following TLR4-mediated activation. Electrophysiology, western blotting, and flow cytometry were used to evaluate Kv1.3 channel presence and TurboID biotinylation activity. We hypothesized that Kv1.3 contains domain-specific interactors that vary during a TLR4-induced inflammatory response, some of which are dependent on the PDZ-binding domain on the C-terminus. We determined that the N-terminus of Kv1.3 is responsible for trafficking Kv1.3 to the cell surface and mitochondria (e.g. NUNDC, TIMM50). Whereas, the C-terminus interacts with immune signaling proteins in an LPS-induced inflammatory response (e.g. STAT1, TLR2, and C3). There are 70 proteins that rely on the C-terminal PDZ-binding domain to interact with Kv1.3 (e.g. ND3, Snx3, and Sun1). Overall, we highlight that the Kv1.3 potassium channel functions beyond conducting the outward flux of potassium ions in an inflammatory context and that KV1.3 modulates activity of key immune signaling proteins, such as STAT1 and C3
2024-05-06 | PXD049433 | Pride
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
Project description:BackgroundThere is a critical need to better understand the mechanisms that drive local cell invasion and metastasis to develop new therapeutics targeting metastatic disease. Bioelectricity is an important mediator of cellular processes and changes in the resting membrane potential (RMP) are associated with increased cancer cell invasion. However, whether the RMP can be used to target invading cancer cells is unknown.MethodsWe employed both genetic and pharmacological manipulation of potassium channel activity and characterized the effects on breast cancer cell migration and invasion in vitro, and metastasis in an animal model of breast cancer.FindingsOur data demonstrate that altering the RMP of triple-negative breast cancer (TNBC) cells by manipulating potassium channel expression increases in vitro invasion, in vivo tumour growth and metastasis, and is accompanied by changes in gene expression associated with cell adhesion.InterpretationWe describe a novel mechanism for RMP-mediated cell migration involving cadherin-11 and the MAPK pathway. Importantly, we identify a new strategy to target metastatic TNBC in vivo by repurposing an FDA-approved potassium channel blocker. Our results demonstrate that bioelectricity regulates cancer cell invasion and metastasis which could lead to a new class of therapeutics for patients with metastatic disease.FundingThis work was supported by the National Institutes of Health (R00-CA207866 to M.J.O.), Tufts University (Start-up funds from the School of Engineering to M.J.O., Tufts Collaborates Award to M.J.O. and M.L.), Allen Discovery centre program (Paul G. Allen Frontiers Group (12,171) to M.L.), and Breast Cancer Alliance Young Investigator Grant to M.J.O, Laidlaw Scholar funding to D.S. M.L. also gratefully acknowledges support of the Barton Family Foundation.
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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