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Inflammatory Co-Regulation of Voltage-Gated Sodium Channels and Na,K-ATPase in Metastatic Breast Cancer
Steven D Scahill1, Kelly Jean Sherman2, Dennis Paul2
1Department of Interdisciplinary Oncology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
Abstract:
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.
Insights
Inflammation, driven by tumor necrosis factor alpha (TNFα), co-regulates sodium transporters like voltage-gated sodium channels (VGSCs) and Na,K-ATPase in metastatic breast cancer, impacting cancer spread.
Area of Science:
- Oncology
- Cell Biology
- Molecular Biology
Background:
- Sodium regulation is increasingly recognized as a key factor in cancer metastasis.
- Voltage-gated sodium channels (VGSCs) and Na,K-ATPase are sodium transporters upregulated in advanced carcinomas, acting as potential drivers of metastasis.
- The regulatory mechanisms and co-expression patterns of these transporters in cancer remain largely unexplored.
Purpose of the Study:
- To investigate the role of the inflammatory mediator tumor necrosis factor alpha (TNFα) in regulating VGSCs and Na,K-ATPase expression in metastatic breast cancer.
- To determine if TNFα co-regulates these sodium transporters at the RNA level.
- To assess the impact of TNFα and sodium transport inhibition on cancer metastasis-like behavior.
Main Methods:
- Utilized an in vitro model of metastatic breast cancer, drawing parallels from sodium transporter regulation in neurons.
- Administered acute and long-term challenges of TNFα to cancer cells.
- Quantified changes in RNA expression for sodium transporter subtypes and protein expression levels of VGSCs and Na,K-ATPase subtypes.
- Evaluated the effects of TNFα and sodium transport-blocking drugs on cellular metastasis-like behavior.
Main Results:
- Acute TNFα challenge increased RNA for sodium transporter subtypes by 20-100%.
- TNFα reduced overall VGSC expression by 20-30% across all time points.
- Long-term TNFα administration altered the expression and localization of Na,K-ATPase α1 and α3 subtypes.
- Both TNFα and sodium transport inhibitors significantly affected metastasis-like cellular behavior.
Conclusions:
- TNFα co-regulates the expression of VGSCs and Na,K-ATPase at the RNA level in metastatic breast cancer.
- This inflammatory-driven regulatory system of sodium transporters is implicated in carcinogenesis and metastasis.
- Targeting this sodium transport system could offer novel therapeutic strategies for metastatic breast cancer.
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