FIGURE 3.

Molecular mechanisms involved in the metastatic behavior promoted by VGSC. Hypoxic conditions in growing tumors promote the incomplete inactivation of VGSC, generating a persistent sodium current (I _Na P), which induces a depolarized resting membrane potential (V _m ), as has been described with Na_V1.5 activity in breast and colon cancer cells (Djamgoz and Onkal, 2013; Guzel et al., 2018). Depolarized V _m stimulates the phospholipid redistribution; reorganization of phosphatidylinositol-bisphosphate and phosphatidylserine activates Rac1 and K-Ras small GTPases, fomenting the F-actin polymerization through the activation of cortactin, Arp2/3 and cofilin, and the activation of the MAPK signaling pathway (Zhou et al., 2015; Yang et al., 2020). On the other hand, VGSC α subunits interact physically with β subunits, NHE-1, and NCX antiporters in localized membranal regions. VGSC activity promotes the activation of NHE-1 and, as a result, the extracellular perimembrane pH is acidified, favoring the protease activity (cathepsins and matrix metalloproteinases) and the degradation of anchoring-extracellular proteins at the leading edge of motile cells (Brisson et al., 2013; Lopez-Charcas et al., 2018). VGSCs also promote the Src kinase activity and the subsequent F-actin polymerization through the phosphorylation of cortactin (Brisson et al., 2013), as well as the activation of the MAPK, JAK/STAT and PKA signaling pathways, involved in cell proliferation, epithelial-mesenchymal transition and invasion (Chioni et al., 2010; House et al., 2015; Li et al., 2022). Increments in local sodium concentration drive to the reversed function of NCX, pumping sodium out and transporting calcium (Ca²⁺) into the cell. In turn, Ca²⁺ inside the cell activates PKC kinase, following by the activation of RAF, MEK and ERK1/2, which are involved in cell proliferation, as reported in endothelial cells (Andrikopoulos et al., 2011). VGSC β subunits also interact with a variety of molecules. β1 has been shown to promote the process outgrowth in breast cancer cells through the activation of a signaling cascade via Fyn kinase (Brackenbury et al., 2008; Nelson et al., 2014), whereas the activity of RhoA in F-actin polymerization is inhibited by the physical interaction with β4 (Bon et al., 2016). Brown boxes indicate a specific molecule, blue boxes stand for signaling pathways. Figure created using BioRender.