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

Authors :
Osbaldo Lopez-Charcas
Lucile Poisson
Oumnia Benouna
Roxane Lemoine
Stéphanie Chadet
Adrien Pétereau
Widad Lahlou
Serge Guyétant
Mehdi Ouaissi
Piyasuda Pukkanasut
Shilpa Dutta
Sadanandan Velu
Pierre Besson
Driffa Moussata
Sébastien Roger
Source :
Cancers; Volume 15; Issue 1; Pages: 46
Publication Year :
2022
Publisher :
MDPI AG, 2022.

Abstract

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 (NaV) 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 α-subunits of NaV 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 NaV1.5) 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 NaV1.5 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 NaV1.5 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 NaV1.5 and NHE-1 represent two promising targetable membrane proteins against the metastatic progression of CRC.

Details

ISSN :
20726694
Volume :
15
Database :
OpenAIRE
Journal :
Cancers
Accession number :
edsair.doi.dedup.....2197f95e7193f0b2123b868aaeabb5e7
Full Text :
https://doi.org/10.3390/cancers15010046