Contribution of voltage-gated sodium channel β-subunits to cervical cancer cells metastatic behavior

BACKGROUND: Voltage-gated sodium (Na(V)) channels are heteromeric proteins consisting of a single pore forming α-subunit associated with one or two auxiliary β-subunits. These channels are classically known for being responsible of action potential generation and propagation in excitable cells; but lately they have been reported as widely expressed and regulated in several human cancer types. We have previously demonstrated the overexpression of Na(V)1.6 channel in cervical cancer (CeCa) biopsies and primary cultures, and its contribution to cell migration and invasiveness. Here, we investigated the expression of Na(V) channels β-subunits (Na(V)βs) in the CeCa cell lines HeLa, SiHa and CaSki, and determined their contribution to cell proliferation, migration and invasiveness. METHODS: We assessed the expression of Na(V)βs in CeCa cell lines by performing RT-PCR and western blotting experiments. We also evaluated CeCa cell lines proliferation, migration, and invasion by in vitro assays, both in basal conditions and after inducing changes in Na(V)βs levels by transfecting specific cDNAs or siRNAs. The potential role of Na(V)βs in modulating the expression of Na(V) α-subunits in the plasma membrane of CeCa cells was examined by the patch-clamp whole-cell technique. Furthermore, we investigated the role of Na(V)β1 on cell cycle in SiHa cells by flow cytometry. RESULTS: We found that the four Na(V)βs are expressed in the three CeCa cell lines, even in the absence of functional Na(V) α-subunit expression in the plasma membrane. Functional in vitro assays showed differential roles for Na(V)β1 and Na(V)β4, the latter as a cell invasiveness repressor and the former as a migration abolisher in CeCa cells. In silico analysis of Na(V)β4 expression in cervical tissues corroborated the downregulation of this protein expression in CeCa vs normal cervix, supporting the evidence of Na(V)β4’s role as a cell invasiveness repressor. CONCLUSIONS: Our results contribute to the recent conception about Na(V)βs as multifunctional proteins involved in cell processes like ion channel regulation, cell adhesion and motility, and even in metastatic cell behaviors. These non-canonical functions of Na(V)βs are independent of the presence of functional Na(V) α-subunits in the plasma membrane and might represent a new therapeutic target for the treatment of cervical cancer. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12935-019-0757-6) contains supplementary material, which is available to authorized users.