Functional activity of voltage-gated sodium channels (VGSC) has been associated to the invasion and metastasis behaviors of prostate, breast and some other types of cancer. We previously reported the functional expression of VGSC in primary cultures and biopsies derived from cervical cancer (CaC). Here, we investigate the relative expression levels of VGSC subunits and its possible role in CaC. Quantitative real-time PCR revealed that mRNA levels of Na V 1.6 a-subunit in CaC samples were~40-fold higher than in noncancerous cervical (NCC) biopsies. A Na V 1.7 a-subunit variant also showed increased mRNA levels in CaC (~20-fold). All four Na V b subunits were also detected in CaC samples, being Na V b1 the most abundant. Proteins of Na V 1.6 and Na V 1.7 a-subunits were immunolocalized in both NCC and CaC biopsies and in CaC primary cultures as well; however, although in NCC sections proteins were mainly relegated to the plasma membrane, in CaC biopsies and primary cultures the respective signal was stronger and widely distributed in both cytoplasm and plasma membrane. Functional activity of Na V 1.6 channels in the plasma membrane of CaC cells was confirmed by whole-cell patch-clamp experiments using Cn2, a Na V 1.6-specific toxin, which blocked 30% of the total sodium current. Blocking of sodium channels VGSC with tetrodotoxin and Cn2 did not affect proliferation neither migration, but reduced by~20% the invasiveness of CaC primary culture cells in vitro assays. We conclude that Na V 1.6 is upregulated in CaC and could serve as a novel molecular marker for the metastatic behavior of this carcinoma.Cervical cancer (CaC) is the third most common female tumor worldwide and the second in developing countries, with an estimated annual incidence of 452,000 cases. 1 In view of the finding that carcinogenic human papillomavirus (HPV) infections cause virtually all CaC cases, recently a new approach for CaC prevention has emerged with the HPV vaccination of younger women (aged 18 years). 2 Despite the highly significant advance that the vaccine itself represents, a mathematical model has predicted an increase in CaC incidence if vaccination is not followed by a continuous Pap smear screening program. 3 Therefore, the finding of effective diagnosis and therapeutic strategies for CaC still remains as a priority.Lately, there has been an increasing amount of evidences that correlate the function of ion channels with several aspects of cancer progression. 4,5 In particular, voltage-gated sodium channels (VGSC) have been clearly associated to invasion and metastasis behaviors in several types of cancer, including breast, colon, lung, ovary and prostate. 6-10 Sodium channels are protein complexes formed by a large a-subunit and smaller auxiliary b-subunits. The a-subunit alone is sufficient to form a functional channel, but its biophysical properties, trafficking and anchoring to the cell membrane are modulated by b-subunits. 11 The VGSC family is composed by nine different a-subunits (Na V 1.1-Na V 1.9) and four bsubunits (Na...

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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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