The Functional Role of Voltage-Gated Sodium Channel Nav1.5 in Metastatic Breast Cancer

Luo, Qianxuan; Wu, Ting; Wu, Wei; Chen, Gong; Luo, Xuan; Jiang, Liping; Tao, Huai; Kang, Shuntong; Deng, Mei

doi:10.3389/fphar.2020.01111

Cited by 26 publications

(21 citation statements)

References 114 publications

(151 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The overexpression of voltage-gated sodium channels has been shown to be associated with metastatic behavior in a variety of human cancers, including breast cancer, prostate cancer, lung cancer, colorectal cancer, cervical cancer, lymphoma, and neuroblastoma (131,132). Overexpression of the neonatal isoform of the voltage-gated sodium channel, Nav1.5 (nNav1.5), is associated with aggressive human breast cancer metastasis and patient death (131,133,134).…”

Section: Brugada Syndrome and Cancersmentioning

confidence: 99%

“…Overexpression of the neonatal isoform of the voltage-gated sodium channel, Nav1.5 (nNav1.5), is associated with aggressive human breast cancer metastasis and patient death (131,133,134). Nav1.5 overexpression increases metastasis and invasiveness of breast cancer cells by altering H+ efflux and promoting epithelial-to-mesenchymal transition and the expression of cysteine cathepsin (132), possibly due to reduced expression of salt-inducible kinase 1 (SIK1) (135). Both neonatal and adult (aNav1.5) forms of Nav1.5 are expressed at the messenger RNA level in colorectal cancer (136) and the SCN5A gene encoding for the Nav1.5 channel protein is an important regulator of the colon cancer invasion network, involving genes that encompass Wnt signaling, cell migration, ectoderm development, response to biotic stimulus, steroid metabolic process, and cell cycle control (137).…”

Section: Brugada Syndrome and Cancersmentioning

confidence: 99%

See 1 more Smart Citation

Brugada Syndrome: Warning of a Systemic Condition?

D'Imperio

Monasky

Micaglio

et al. 2021

Front. Cardiovasc. Med.

View full text Add to dashboard Cite

Brugada syndrome (BrS) is a hereditary disorder, characterized by a specific electrocardiogram pattern and highly related to an increased risk of sudden cardiac death. BrS has been associated with other cardiac and non-cardiac pathologies, probably because of protein expression shared by the heart and other tissue types. In fact, the most commonly found mutated gene in BrS, SCN5A, is expressed throughout nearly the entire body. Consistent with this, large meals and alcohol consumption can trigger arrhythmic events in patients with BrS, suggesting a role for organs involved in the digestive and metabolic pathways. Ajmaline, a drug used to diagnose BrS, can have side effects on non-cardiac tissues, such as the liver, further supporting the idea of a role for organs involved in the digestive and metabolic pathways in BrS. The BrS electrocardiogram (ECG) sign has been associated with neural, digestive, and metabolic pathways, and potential biomarkers for BrS have been found in the serum or plasma. Here, we review the known associations between BrS and various organ systems, and demonstrate support for the hypothesis that BrS is not only a cardiac disorder, but rather a systemic one that affects virtually the whole body. Any time that the BrS ECG sign is found, it should be considered not a single disease, but rather the final step in any number of pathways that ultimately threaten the patient's life. A multi-omics approach would be appropriate to study this syndrome, including genetics, epigenomics, transcriptomics, proteomics, metabolomics, lipidomics, and glycomics, resulting eventually in a biomarker for BrS and the ability to diagnose this syndrome using a minimally invasive blood test, avoiding the risk associated with ajmaline testing.

show abstract

Section: Brugada Syndrome and Cancersmentioning

confidence: 99%

Section: Brugada Syndrome and Cancersmentioning

confidence: 99%

Brugada Syndrome: Warning of a Systemic Condition?

D'Imperio

Monasky

Micaglio

et al. 2021

Front. Cardiovasc. Med.

View full text Add to dashboard Cite

show abstract

“…Previously it has been reported that breast cancer cells are less negative than their normal counterparts and that blocking sodium channels inhibits cell migration and invasion in MDA-MB-231 and MCF7 cells 9,47,48 , however if these effects are RMPdependent is not noted. In contrast, our results suggest that hyperpolarization via K + channel expression leads to increased breast cancer cell invasion.…”

Section: Discussionmentioning

confidence: 96%

Potassium channel-driven bioelectric signaling regulates metastasis in triple-negative breast cancer

et al. 2021

Preprint

View full text Add to dashboard Cite

There 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, the mechanism is not well understood. Our data demonstrate that altering the RMP of triple-negative breast cancer (TNBC) cells by manipulating potassium channel expression increases in vitro invasion, in vivo tumor growth, and metastasis, and is accompanied by 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 strategy to target metastatic TNBC in vivo by repurposing FDA-approved potassium channel blockers. Our results provide an understanding of the mechanisms by which bioelectricity regulates cancer cell invasion and metastasis that could lead to a new class of therapeutics for patients with metastatic disease.

show abstract

“…Ion channels have been previously shown to regulate tumour cell migration. Indeed, blocking sodium channels inhibits cell migration and invasion in MDA-MB-231 and MCF7 breast cancer cells, 9 , 69 , 70 however whether these effects are RMP-dependant is not discussed. Several potassium channels that are known to impact K + currents have also been linked to migration.…”

Section: Discussionmentioning

confidence: 99%

Potassium channel-driven bioelectric signalling regulates metastasis in triple-negative breast cancer

et al. 2022

View full text Add to dashboard Cite

Summary Background There 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. Methods We 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. Findings Our 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. Interpretation We 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. Funding This 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.

show abstract

The Functional Role of Voltage-Gated Sodium Channel Nav1.5 in Metastatic Breast Cancer

Cited by 26 publications

References 114 publications

Brugada Syndrome: Warning of a Systemic Condition?

Brugada Syndrome: Warning of a Systemic Condition?

Potassium channel-driven bioelectric signaling regulates metastasis in triple-negative breast cancer

Potassium channel-driven bioelectric signalling regulates metastasis in triple-negative breast cancer

Contact Info

Product

Resources

About