SCN5A promotes the growth and lung metastasis of triple-negative breast cancer through EF2-kinase signaling

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer often associated with early metastasis, poor prognosis, and shortened survival. The main causes of its high mortality level are attributed to significant genetic heterogenity, rapid development of chemoresistance, and a limited number of targeted therapeutics. Therefore, as described herein, we investigated the role of the SCN5A gene encoding the voltage-gated sodium ion channel NaV1.5 in vitro and in vivo in TNBC models. Cell proliferation, colony formation, invasion, western blot and in vivo analyzes were performed. We found that SCN5A gene/NaV1.5 and its neonatal spliced isoform nNaV1.5 were markedly upregulated in TNBC cells and that they promoted cell proliferation, colony formation, motility/migration, and invasion. Therapeutic targeting of NaV1.5/nNaV1.5 via systemic in-jection of specific siRNAs incorporated in single-lipid nanoparticles suppressed tumor growth and lung metastasis in orthotopic TNBC models. We further demonstrated that targeting of NaV1.5/nNaV1.5 expression associated with eukaryotic elongation factor-2 kinase (EF2K) expression. This approach led to the inhibition EF2K's oncogenic signaling and its clinically significant downstream targets, including integrin beta 1/Src/focal adhesion kinase, c-myc, cyclin D1, phosphoinositide 3-kinase/Akt, p-ERK, p-IF2 alpha and p-PI3K. Targeting of NaV1.5/ nNaV1.5 also induced robust apoptosis in TNBCs in vivo. Inhibition of both isoforms of SCN5A in TNBC cells enhanced the effect of first-line chemotherapeutics such as paclitaxel. In conclusion, our results provide the first evidence that expression of SCN5A has an important role in the growth of primary and lung-metastatic TNBCs and that targeting of NaV1.5/nNaV1.5 by systemically administered therapeutics is a potential molecularly tar-geted strategy to control TNBC progression and may enhance the efficacy of currently used chemotherapeutics.