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Targeting KV10.1 Channels in Breast Cancer: The Role of Ion Channel Genetics in In Silico Electrophysiological Mechanisms and Drug Discovery

Biochemical/Metabolic and Therapeutics
  • Primary Categories:
    • Basic Research
  • Secondary Categories:
    • Basic Research
Introduction:
Ion channel genetics has emerged as a critical area of study in cancer biology, revealing significant contributions of ion channels to tumor progression. Among these, the voltage-gated potassium channel KV10.1 (Eag1) is increasingly recognized for its oncogenic role in breast cancer. KV10.1 overexpression in breast cancer cells is associated with enhanced motility, unchecked proliferation, and apoptosis resistance—processes vital to tumor growth and metastasis. Furthermore, KV10.1 has been implicated in the epithelial-to-mesenchymal transition (EMT), a hallmark of cancer metastasis, and in modulating immune interactions within the tumor microenvironment. These interactions may influence immune surveillance and evasion. Despite these insights, the precise electrophysiological mechanisms underlying KV10.1’s role in cancer remain underexplored, limiting its therapeutic exploitation. Bridging this knowledge gap could unlock novel treatments that simultaneously disrupt cancer progression and enhance immune responses.

Methods:
This study leverages computational and in silico approaches to investigate KV10.1’s functional properties in breast cancer cells. Advanced molecular docking simulations and electrophysiological modeling were used to analyze the channel’s impact on membrane potential, ion flux, and cancer cell responses under various conditions. Structural and functional predictions were cross-validated with experimental data to ensure accuracy. Key computational objectives included identifying specific inhibitors of KV10.1 and simulating their effects on channel activity. Binding affinities of inhibitors were evaluated through molecular docking, while gating kinetics, ion conductance, and current properties were examined to differentiate cancer cell behavior from normal cells. Inhibitor efficacy was modeled in restoring normal electrophysiological states and disrupting oncogenic pathways.

Results:
Computational models revealed significant differences in KV10.1 channel behavior between breast cancer cells and normal cells. In cancer cells, KV10.1 exhibited altered gating kinetics and increased ion conductance, contributing to hyperpolarized membrane potential states. This shift in membrane potential (-25 mV) enhanced cellular excitability and metastatic potential. KV10.1 overexpression in cancer cells disrupted normal ion flux, favoring conditions for increased cell proliferation and migration. Molecular docking identified several promising KV10.1 inhibitors, including a notable class of tricyclic antidepressants. These inhibitors demonstrated strong binding affinities and high selectivity for KV10.1. At nanomolar concentrations, they successfully restored the resting membrane potential in silico, reversing cancer-associated electrophysiological changes. This restoration could potentially impair EMT, reduce metastatic capability, and disrupt other oncogenic signaling pathways. Moreover, the study underscored KV10.1’s potential role in immune system modulation within the tumor microenvironment. By altering ion channel activity, KV10.1 inhibition may enhance immune system recognition of cancer cells, supporting broader immune engagement and reducing tumor immune evasion.

Conclusion:
This research emphasizes the pivotal role of KV10.1 channels in breast cancer electrophysiology and their viability as a therapeutic target. The computational models demonstrate that selective inhibition of KV10.1 disrupts key oncogenic pathways, reduces metastatic behavior, and potentially enhances immune system engagement. Findings suggest that tricyclic antidepressants, acting as KV10.1 inhibitors, present a promising therapeutic avenue by restoring normal ion channel activity and impairing tumor progression. By integrating computational predictions with experimental evidence, this research advances our understanding of KV10.1’s oncogenic mechanisms and therapeutic potential. Targeting KV10.1 channels represents a transformative strategy in breast cancer management, addressing metastasis and immune system dynamics. Insights from this study underscore the broader significance of ion channel genetics in cancer biology, highlighting pathways that can be exploited for innovative, precision-targeted therapies. Future experimental and clinical studies are essential to validate these findings and explore the broader implications of ion channel genetics in cancer treatment.

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