Inflammatory Co-Regulation of Voltage-Gated Sodium Channels and Na,K-ATPase in Metastatic Breast Cancer

Sodium regulation is a potentially major driver of cancer metastasis. Voltage-gated sodium channels (VGSCs) and Na,K-ATPase are sodium transporters that are upregulated in many advanced carcinomas and are implicated as metastatic drivers. However, little is known about what drives this overexpression, how these proteins influence metastatic behavior, or whether these complementary sodium transporters are co-regulated in cancer. Using sodium transporter regulation in healthy neurons as a model, the present study demonstrated that the inflammatory mediator tumor necrosis factor alpha (TNFα) affects the expression of VGSCs and Na,K-ATPase in an in vitro model of metastatic breast cancer. Acute TNFα challenge increased RNA for sodium transporter subtypes by 20-100%, TNFα reduced the overall expression of VGSCs by 20-30% at all time-points examined, and long-term administration increased nuclear localization of the α1 subtype of Na,K-ATPase while increasing the overall expression of the α3 subtype. This study established that VGSCs and Na,K-ATPase are co-regulated by TNFα at the RNA level, and it was demonstrated that both TNFα and sodium transport-blocking drugs can significantly impact cellular metastasis-like behavior. Together these data are evidence that inflammation in metastatic breast cancer co-regulates the expression of VGSCs and Na,K-ATPase, and this regulatory system may contribute to carcinogenesis.