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

Abstract

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.

Analysis of the effect of the scorpion toxin AaH-II on action potential generation in the axon initial segment

“…Mutations of VGNC genes are at the origin of a variety of channelopathies [34,35] making VGNC potential interesting targets for future therapies [36]. In addition, VGNCs are the potential targets of novel treatments for cancer [37] and inflammation-related diseases [38]. The present study represents a proof-of-principle on how our high-resolution imaging approach to explore AP generation in the AIS can be used to obtain relevant information on therapeutic candidates targeting VGNCs.…”

Therapeutic targeting of voltage-gated sodium channel NaV1.7 for cancer metastasis

“…The structure of eukaryotic VGSCs is conserved with >50% sequence homology across the nine subtypes ( de Lera Ruiz and Kraus, 2015 ; Sanchez-Sandoval et al, 2023 ). The structure of VGSC consists of an alpha (α) subunit which contains four large homologous Domains (DI-DIV) [ Figure 1A ] with approximately 2000 amino acid residues (MW ∼260 kDa) ( William et al, 2005 ), and one or two beta (β) auxiliary subunits which consist of approximately 220 amino acid residues per unit (MW 30–40 kDa) ( de Lera Ruiz and Kraus, 2015 ; Deuis et al, 2017 ; Salvage et al, 2020 ; Sayers et al, 2022 ).…”

“…Even though the mechanism of the involvement VGSCs in cancer progression and metastasis has not been fully resolved, recent literature suggests that the overexpression of different VGSC subtypes facilitate cell motility by increasing ECM protease secretion, cell migration and invasion, invadopodia formation, activation of Src kinases, MAPK kinases, and modulation of Jak/Stat and PKA signaling pathways. These are key processes that enhance cell proliferation, epithelial-mesenchymal transition (EMT) and cell invasion ( Brisson et al, 2013 ; Besson et al, 2015 ; Roger et al, 2015 ; Angus and Ruben, 2019 ; Sanchez-Sandoval et al, 2023 ). A summary of potential mechanisms of action (MoA) of Na V 1.7 promoting invasive effects is presented in Figure 4 .…”