The Voltage-Gated Sodium Channel Beta4 Subunit Maintains Epithelial Phenotype in Mammary Cells

Doray, Adélaïde; Lemoine, Robert; Severin, Marc; Chadet, Stéphanie; Lopez‐Charcas, Osbaldo; Héraud, Audrey; Baron, Christophe; Besson, Pierre; Monteil, Arnaud; Pedersen, Stine Falsig; Roger, Sébastien

doi:10.3390/cells10071624

Cited by 3 publications

(2 citation statements)

References 44 publications

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“…This effect was associated with an increased degradation of β-catenin, reduced E-cadherin expression, and induction of mesenchymal markers such as N-cadherin, vimentin, and α-SMA. With this experimental evidence, authors conclude that β4-subunit downregulation might be a determining step in early carcinogenesis (Doray et al, 2021).…”

Section: Morphology and Migrationmentioning

confidence: 86%

Voltage-gated sodium channels: from roles and mechanisms in the metastatic cell behavior to clinical potential as therapeutic targets

2023

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During the second half of the last century, the prevalent knowledge recognized the voltage-gated sodium channels (VGSCs) as the proteins responsible for the generation and propagation of action potentials in excitable cells. However, over the last 25 years, new non-canonical roles of VGSCs in cancer hallmarks have been uncovered. Their dysregulated expression and activity have been associated with aggressive features and cancer progression towards metastatic stages, suggesting the potential use of VGSCs as cancer markers and prognostic factors. Recent work has elicited essential information about the signalling pathways modulated by these channels: coupling membrane activity to transcriptional regulation pathways, intracellular and extracellular pH regulation, invadopodia maturation, and proteolytic activity. In a promising scenario, the inhibition of VGSCs with FDA-approved drugs as well as with new synthetic compounds, reduces cancer cell invasion in vitro and cancer progression in vivo. The purpose of this review is to present an update regarding recent advances and ongoing efforts to have a better understanding of molecular and cellular mechanisms on the involvement of both pore-forming α and auxiliary β subunits of VGSCs in the metastatic processes, with the aim at proposing VGSCs as new oncological markers and targets for anticancer treatments.

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Section: Morphology and Migrationmentioning

confidence: 86%

Voltage-gated sodium channels: from roles and mechanisms in the metastatic cell behavior to clinical potential as therapeutic targets

2023

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“…In the last three decades, studies have shed light on the signaling pathways and mechanisms involving these membrane proteins in cancer cells which, for β-subunits, concern enhanced vascularization and tumor growth, the promotion of a bipolar cell morphology and a hybrid aggressive mesenchymal-amoeboid phenotype, but also a reduction of cell adhesion to the substrate, cell-to-cell contacts and apoptosis [7,10,11]. On the other hand, the mechanisms described for the α-subunits in cancer include the dysregulation of sodium homeostasis, depolarization of the cell membrane, F-actin polymerization, invadopodial formation, Na + /H + exchanger type 1 (NHE-1) allosteric modulation and enhanced secretion and activity of extracellular matrix proteases [7,[12][13][14][15][16][17].…”

Section: Introductionmentioning

confidence: 99%

Voltage-Gated Sodium Channel NaV1.5 Controls NHE−1−Dependent Invasive Properties in Colon Cancer Cells

Lopez‐Charcas

Poisson

Benouna

et al. 2022

Cancers

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Colorectal cancer (CRC) is the second leading cause of death worldwide, with 0.9 million deaths per year. The metastatic stage of the disease is identified in about 20% of cases at the first diagnosis and is associated with low patient-survival rates. Voltage-gated sodium channels (NaV) are abnormally overexpressed in several carcinomas including CRC and are strongly associated with the metastatic behavior of cancer cells. Acidification of the extracellular space by Na+/H+ exchangers (NHE) contributes to extracellular matrix degradation and cell invasiveness. In this study, we assessed the expression levels of pore-forming α-subunits of NaV channels and NHE exchangers in tumor and adjacent non-malignant tissues from colorectal cancer patients, CRC cell lines and primary tumor cells. In all cases, SCN5A (gene encoding for NaV1.5) was overexpressed and positively correlated with cancer stage and poor survival prognosis for patients. In addition, we identified an anatomical differential expression of SCN5A and SLC9A1 (gene encoding for NHE-1) being particularly relevant for tumors that originated on the sigmoid colon epithelium. The functional activity of NaV1.5 channels was characterized in CRC cell lines and the primary cells of colon tumors obtained using tumor explant methodologies. Furthermore, we assessed the performance of two new small-molecule NaV1.5 inhibitors on the reduction of sodium currents, as well as showed that silencing SCN5A and SLC9A1 substantially reduced the 2D invasive capabilities of cancer cells. Thus, our findings show that both NaV1.5 and NHE-1 represent two promising targetable membrane proteins against the metastatic progression of CRC.

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The histone methyltransferase KMT2D is essential for embryo implantation via regulating precise differentiation of endometrial cells

Kobayashi,

Tajika,

Kohmaru

et al. 2024

Cell Death Discov.

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Embryo implantation failures are a major challenge in reproductive medicine, but the underlying mechanism remains poorly understood. Successful implantation requires dynamic remodeling of the endometrium through integrated proliferation and differentiation of endometrial cells including luminal epithelial, glandular epithelial, and stromal cells. Conversely, their disruption causes infertility. Spatiotemporal control of transcription is required for these processes; however, the underlying epigenetic regulation is largely unknown. In this study, we examined expression data from the human endometrium during implantation and discovered that expression of the histone lysine methyltransferase KMT2D was significantly suppressed in patients with recurrent implantation failure. Further study revealed that uterine deletion of Kmt2d in mice caused infertility due to implantation failure. Morphological analysis discovered a reduction in the number of uterine glands and aberrant differentiation of the luminal and glandular epithelium into stratified phenotypes in Kmt2d knockout uteri. Administration of leukemia inhibitory factor protein, which is expressed in uterine glands and is essential for implantation, did not rescue implantation failure in Kmt2d knockout mice, suggesting that infertility was not solely due to uterine gland dysfunction. RNA sequencing analysis revealed that Kmt2d knockout uteri displayed suppressed expression of genes involved in ion homeostasis, which may affect the uterine luminal morphology. Our study suggests that KMT2D plays an essential role in facilitating successful embryo implantation by regulating the coordinated differentiation of endometrial cells, providing valuable insights into unexplained implantation failures in women.

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The Voltage-Gated Sodium Channel Beta4 Subunit Maintains Epithelial Phenotype in Mammary Cells

Cited by 3 publications

References 44 publications

Voltage-gated sodium channels: from roles and mechanisms in the metastatic cell behavior to clinical potential as therapeutic targets

Voltage-gated sodium channels: from roles and mechanisms in the metastatic cell behavior to clinical potential as therapeutic targets

Voltage-Gated Sodium Channel NaV1.5 Controls NHE−1−Dependent Invasive Properties in Colon Cancer Cells

The histone methyltransferase KMT2D is essential for embryo implantation via regulating precise differentiation of endometrial cells

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