Abstract

Abstract ID 95047

Poster Board 448

Voltage-gated sodium channels (VGSCs) and Na,K-ATPase are two targets implicated in the metastatic progression in cancer. Both are upregulated in a variety of aggressive cancers and have been shown to correlate with invasiveness in vitro and metastasis in vivo. Despite their potentially significant role in cancerous progression, however, little is known as to what drives their overexpression in cancer cells, how they contribute to a metastatic phenotype, or whether these proteins that have complementary activity on sodium ions are co-regulated in cancer. This study provides evidence of inflammatory regulation of VGSCs and Na,K-ATPase in the metastatic breast cancer cell line, MDA-MB-231. Acute administration of TNF α increases RNA for clinically relevant VGSC (Nav1.5) and Na,K-ATPase (α1 and α3) subtypes by approximately 1.2-2 fold. The inflammatory effect on Na,K-ATPase is dependent on the expression and ion-transporting function of Nav1.5, while the inflammatory effect on Nav1.5 is independent of Na,K-ATPase expression. However, the results of siRNA knockdown and ion-blocking drug studies suggest a more complex regulatory intermingling of these two transporters. TNF α challenge also affects the protein localization and overall expression levels of VGSCs and Na,K-ATPase in MDA-MB-231 cells, and drives aggressive behavior of the cells in vitro. These inflammatory effects can be disrupted by addition of VGSC or Na,K-ATPase blocking drugs. In total, these studies demonstrate inflammatory regulation of VGSCs and Na,K-ATPase in metastatic breast cancer cells at the RNA and protein levels, as well as a sophisticated co-regulation of the two transporters at the RNA level. The results may help elucidate the complex factors that drive VGSC and Na,K-ATPase expression in metastatic cancer cells and their effect on cancerous behavior.

This research was funded by a Research Services Contract from Oleander Medical Technologies to DP.