Effect of Sigma-1 Receptors on Voltage-Gated Sodium Ion Channels in Colon Cancer Cell Line SW620.

Abstract

Background: Voltage-gated sodium channels (VGSCs) play pivotal roles in the metastatic process in several cancers, including breast and colon cancers. Sigma-1 receptors are known to interact and form complexes with a number of ion channels aiding the delivery of the channel protein to the plasma membrane. Drugs that bind the Sigma-1 receptor are hypothesized to affect this process and reduce the delivery of the channel protein to the plasma membrane, in turn reducing the metastatic potential of the cells. Methods: Human colon cancer cell line SW620 was utilized as a model to investigate the interaction between the neonatal VGSC (nNav1.5) and the Sigma-1 receptor. This was accomplished using drugs that bind the Sigma-1 receptor, Sigma-1 receptor silencing, and antibodies that bind and block the nNav1.5 channel. Results: Sigma-1 receptor drugs SKF10047 and dimethyl tryptamine were found to alter (reduce) the adhesion of these cells by 46-54% at a 20 μM drug concentration. In a similar manner, gene silencing of the Sigma-1 receptor had a similar effect in reducing the adhesion of these cells to collagen-coated plates by 30%. The Sigma-1 receptor was found to be in a complex with nNav1.5 in SW620 cells, and Sigma-1 drugs or gene silencing of the Sigma-1 receptor results in a reduction of the surface expression of nNav1.5 by ∼50%. Culture of SW620 cells under hypoxic conditions resulted in upregulation of the Sigma-1 receptor and nNav1.5. In addition, surface expression of nNav1.5 protein increased under hypoxic culture conditions and this was inhibited by the application of SKF10047. Conclusions: It is proposed that in colon cancer cells, upregulated Sigma-1 receptor expression in hypoxia led to increased nNav1.5 protein expression at the plasma membrane and resulted in the cells switching to a more invasive state.