Sodium Channel Nav1.5 Controls Epithelial-to-Mesenchymal Transition and Invasiveness in Breast Cancer Cells Through its Regulation by the Salt-Inducible Kinase-1

Abstract

Loss of epithelial polarity and gain in invasiveness by carcinoma cells are critical events in the aggressive progression of cancers and depend on phenotypic transition programs such as the epithelial-to-mesenchymal transition (EMT). Many studies have reported the aberrant expression of voltage-gated sodium channels (NaV) in carcinomas and specifically the NaV1.5 isoform, encoded by the SCN5A gene, in breast cancer. NaV1.5 activity, through an entry of sodium ions, in breast cancer cells is associated with increased invasiveness, but its participation to the EMT has to be clarified. In this study, we show that reducing the expression of NaV1.5 in highly aggressive human MDA-MB-231 breast cancer cells reverted the mesenchymal phenotype, reduced cancer cell invasiveness and the expression of the EMT-promoting transcription factor SNAI1. The heterologous expression of NaV1.5 in weakly invasive MCF-7 breast cancer cells induced their expression of both SNAI1 and ZEB1 and increased their invasive capacities. In MCF-7 cells the stimulation with the EMT-activator signal TGF-β1 increased the expression of SCN5A. Moreover, the reduction of the salt-inducible kinase 1 (SIK1) expression promoted NaV1.5-dependent invasiveness and expression of EMT-associated transcription factor SNAI1. Altogether, these results indicated a prominent role of SIK1 in regulating NaV1.5-dependent EMT and invasiveness.

Rock inhibition promotes NaV1.5 sodium channel-dependent SW620 colon cancer cell invasiveness

“…Voltage-gated sodium channels (Na V ) have been demonstrated to be critical inductors of carcinoma cell invasiveness 37 , 38 . In colon 30 – 32 as in breast cancer 36 , 39 – 43 , the Na V 1.5 isoform has been identified to be abnormally upregulated and associated with invasive and metastatic potencies, and to control cell morphology. Its inhibition leads to an increased circularity in breast cancer cells 36 , 40 , while its expression and activity promotes the acquisition of an elongated mesenchymal phenotype 43 .…”

The Functional Role of Voltage-Gated Sodium Channel Nav1.5 in Metastatic Breast Cancer

“…Salt-inducible kinase 1 (SIK1) has been identified as an important factor in regulating sodium homeostasis and as a tumor repressor that participates in the progression of cancer cells (Sjostrom et al, 2007;Selvik et al, 2014). Lower expression of SIK1 was observed in different breast tumor grades than in normal tissues (Gradek et al, 2019). Silencing SIK1 upregulates SCN5A expression and increases H + outflow, thus, improving invasiveness (Gradek et al, 2019).…”

“…Lower expression of SIK1 was observed in different breast tumor grades than in normal tissues ( Gradek et al, 2019 ). Silencing SIK1 upregulates SCN5A expression and increases H + outflow, thus, improving invasiveness ( Gradek et al, 2019 ). TGF-β1 is a well-known inducer of epithelial-to-mesenchymal transition (EMT) and a multifunctional regulatory factor affecting cancer development ( Jakowlew, 2006 ; Moustakas and Heldin, 2016 ).…”

“…TGF-β1 is a well-known inducer of epithelial-to-mesenchymal transition (EMT) and a multifunctional regulatory factor affecting cancer development ( Jakowlew, 2006 ; Moustakas and Heldin, 2016 ). Weakly metastatic MCF-7 cells treated with TGF-β1 demonstrated increased expression of SCN5A and induction of invasion ( Gradek et al, 2019 ). Epidermal growth factor (EGF) signals have been confirmed to be overexpressed and are involved in the development of breast cancer ( Adams et al, 2009 ; Yao et al, 2012 ).…”

“…In contrast, MCF-7 cells overexpressing Nav1.5 display an increased invasive capacity, as well as an increased expression level of SNAI1, which provides evidence for the role of SNAI1 in Nav1.5 activity-mediated invasive process of breast cancer. Indeed, loss of expression of SIK1 upregulates Nav1.5 activity and expression ( Gradek et al, 2019 ). Hence, it is that low expression levels of SIK1 in breast cancer cells induce the activity and expression of Nav1.5, followed by high expression of SNAI1, triggering the EMT and metastasis observed in breast cancer cells.…”