Voltage-Gated Sodium Channel NaV1.5 Controls NHE-1-Dependent Invasive Properties in Colon Cancer Cells

Simple Summary Colorectal cancer is a major cause of morbidity and mortality that affects men and women equally. Here, we present the role of voltage-gated sodium channels (Na-V) and Sodium/hydrogen exchanger type 1 (NHE-1) in conferring invasive capabilities to colorectal cancer cells. We also study how pharmacological inhibition or suppression of their expression by siRNA modifies the aggressive cancer cell phenotype. Our findings suggest that Na-V channels and NHE-1 are pertinent molecular targets for cancer therapy. Colorectal cancer (CRC) is the second leading cause of death worldwide, with 0.9 million deaths per year. The metastatic stage of the disease is identified in about 20% of cases at the first diagnosis and is associated with low patient-survival rates. Voltage-gated sodium channels (Na-V) are abnormally overexpressed in several carcinomas including CRC and are strongly associated with the metastatic behavior of cancer cells. Acidification of the extracellular space by Na+/H+ exchangers (NHE) contributes to extracellular matrix degradation and cell invasiveness. In this study, we assessed the expression levels of pore-forming alpha-subunits of Na-V channels and NHE exchangers in tumor and adjacent non-malignant tissues from colorectal cancer patients, CRC cell lines and primary tumor cells. In all cases, SCN5A (gene encoding for Na(V)1.5) was overexpressed and positively correlated with cancer stage and poor survival prognosis for patients. In addition, we identified an anatomical differential expression of SCN5A and SLC9A1 (gene encoding for NHE-1) being particularly relevant for tumors that originated on the sigmoid colon epithelium. The functional activity of Na(V)1.5 channels was characterized in CRC cell lines and the primary cells of colon tumors obtained using tumor explant methodologies. Furthermore, we assessed the performance of two new small-molecule Na(V)1.5 inhibitors on the reduction of sodium currents, as well as showed that silencing SCN5A and SLC9A1 substantially reduced the 2D invasive capabilities of cancer cells. Thus, our findings show that both Na(V)1.5 and NHE-1 represent two promising targetable membrane proteins against the metastatic progression of CRC.