Abstract
Potassium ion channels are critical in the regulation of cell motility. The acquisition of cell motility is an essential parameter of cancer metastasis. However, the role of K+ channels in cancer metastasis has been poorly studied. High expression of the hG1 gene, which encodes for Kv11.1 channel associates with good prognosis in estrogen receptor-negative breast cancer (BC). We evaluated the efficacy of the Kv11.1 activator NS1643 in arresting metastasis in a triple negative breast cancer (TNBC) mouse model. NS1643 significantly reduces the metastatic spread of breast tumors in vivo by inhibiting cell motility, reprogramming epithelial–mesenchymal transition via attenuation of Wnt/β-catenin signaling and suppressing cancer cell stemness. Our findings provide important information regarding the clinical relevance of potassium ion channel expression in breast tumors and the mechanisms by which potassium channel activity can modulate tumor biology. Findings suggest that Kv11.1 activators may represent a novel therapeutic approach for the treatment of metastatic estrogen receptor-negative BC. Ion channels are critical factor for cell motility but little is known about their role in metastasis. Stimulation of the Kv11.1 channel suppress the metastatic phenotype in TNBC. This work could represent a paradigm-shifting approach to reducing mortality by targeting a pathway that is central to the development of metastases.
Highlights
Breast cancer (BC) is a heterogeneous disease both biologically and clinically[1]
NS1643-mediated stimulation of Kv11.1 activity inhibits breast tumor metastasis In order to examine whether stimulation of Kv11.1 channel activity would inhibit BC growth and metastasis in vivo, we established human-derived triple negative breast cancer (TNBC) xenograft tumors using MDA-MB-231 BC cells in NOD-scid IL2Rγnull (NSG) mice[24]
Control mice exhibited metastasis in both lobes of the liver, whereas liver metastases were confined to a single lobe of the liver in mice treated with NS1643
Summary
Tumor biology and clinical outcome are heavily influenced by the expression of proteins involved in estrogen-dependent signaling and the human epidermal growth factor receptor, type 2 (HER2) signaling pathway. Therapeutic strategies that target the estrogen receptor (ER) and HER2 signaling have improved survival for patients with ER-positive and HER2 over-expressing BC2, but tumors that do not express these often have a poor outcome. All living cells are electrically polarized owing to a variety of ion channels and transport proteins in the cell membrane that control intracellular ion concentrations. Transmembrane ionic gradients determine membrane excitability, which regulates important cellular events including generation and transmission neuronal electrical signals and muscle contraction[3,4]. Potassium (K+) channels can control the phenotypic switch from an epithelial state to a mesenchymal phenotype (epithelial–mesenchymal transition; EMT)[11,12], leading to Official journal of the Cell Death Differentiation Association
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