Voltage-gated sodium channels and metastatic disease

Abstract

Voltage-gated Na (+) channels (VGSCs) are macromolecular protein complexes containing a pore-forming α subunit and smaller non-pore-forming β subunits. VGSCs are expressed in metastatic cells from a number of cancers. In these cells, Na (+) current carried by α subunits enhances migration, invasion and metastasis in vivo. In contrast, the β subunits mediate cellular adhesion and process extension. The prevailing hypothesis is that VGSCs are upregulated in cancer, in general favoring an invasive/metastatic phenotype, although the mechanisms are still not fully clear. Expression of the Nav 1.5 α subunit associates with poor prognosis in clinical breast cancer specimens, suggesting that VGSCs may have utility as prognostic markers for cancer progression. Furthermore, repurposing existing VGSC-blocking therapeutic drugs may provide a new strategy to improve outcomes in patients suffering from metastatic disease, which is the major cause of cancer-related deaths, and for which there is currently no cure.

Figure 1. Multifunctional interactions of VGSCs. Basic topology of the pore-forming α subunit is shown, consisting of four homologous domains each containing six transmembrane segments. Segment four contains the voltage sensor. The smaller β subunits contain an extracellular immunoglobulin (Ig) loop, transmembrane domain and an intracellular C-terminal domain. β1 and β3 are non-covalently linked to the α subunit, whereas, β2 and β4 are covalently linked through disulfide bonds. The alternative splice variant, β1B, lacks a transmembrane domain. α subunits interact with a number of other signaling molecules, including p11, protein kinase A (PKA), protein kinase C (PKC), ankyrin G, MOG1, fibroblast growth factor-homologous factor 1B (FHF1B), calmodulin, NEDD4,^, syntrophin and dystrophin. Several of the β subunits interact with other cell adhesion molecules and regulatory proteins, including tenascin C, tenascin R,^, contactin, N-cadherin, neurofascin (NF)155, NF186, NrCAM, ankyrin G, receptor protein tyrosine phosphatase β (RPTPβ), PKA and fyn kinase. The β subunits are substrates for proteolytic cleavage by α-secretase, BACE1 and γ-secretase.^, The intracellular domain of β2 is proposed to regulate gene expression in the nucleus. ψ, glycosylation sites. Figure was produced using Science Slides 2006 software.

Figure 2. α subunit involvement in pH-dependent cellular invasion. Na⁺ influx through Na_v1.5 is proposed to activate the Na⁺/H⁺ exchanger NHE1, co-expressed with Na_v1.5 in lipid rafts contained within the caveolae of invasive breast cancer cells. Increased NHE1 activity results in increased H⁺ efflux, which, in turn, enhances proteolytic activity of cysteine cathepsins B and S, which degrade the extracellular matrix, permitting invasion.^, The mechanism by which Na_v1.5 enhances NHE1 is not yet clear. Figure was produced using Science Slides 2006 software.

Figure 3. Na_v1.5-regulated gene transcriptional network controlling invasion. Oval nodes represent regulatory genes, gray boxes represent effector genes and white boxes represent gene ontology categories. Arrows indicate activation and tees show repression. Reprinted by permission from the American Association for Cancer Research: House CD et al., Voltage-gated Na⁺ channel SCN5A is a key regulator of a gene transcriptional network that controls colon cancer invasion. Cancer Res 2010; 70:6957-67; PMID:20651255.

Figure 4. Neurite outgrowth and excitability regulated by β1 and Na_v1.6. (A) β1-mediated neurite outgrowth is inhibited by the Scn8a null-mutation. Neurite lengths of wild-type and Scn8a-null cerebellar granule neurons grown on monolayers of control and b1-expressing fibroblasts. Data are mean and SEM ***p < 0.001. (B) Proposed model for Na⁺ current reciprocal involvement in β1-mediated neurite outgrowth. Complexes containing Na_v1.6, β1 and contactin are present throughout the neuronal membrane in the soma, neurite and growth cone. Na⁺ influx is required for β1-mediated neurite extension and migration. VGSC complexes along the neurite participate in cell-cell adhesion and fasciculation. β1 is also required for Na_v1.6 expression at the axon initial segment, and subsequent high-frequency action potential firing. Electrical activity may further promote β1-mediated neurite outgrowth at or near the growth cone. Figure reproduced with permission.