Pharmacological Activation of Potassium Channel Kv11.1 with NS1643 Attenuates Triple Negative Breast Cancer Cell Migration by Promoting the Dephosphorylation of Caveolin-1

Abstract

The prevention of metastasis is a central goal of cancer therapy. Caveolin-1 (Cav-1) is a structural membrane and scaffolding protein shown to be a key regulator of late-stage breast cancer metastasis. However, therapeutic strategies targeting Cav-1 are still lacking. Here, we demonstrate that the pharmacological activation of potassium channel Kv11.1, which is uniquely expressed in MDA-MB-231 triple negative breast cancer cells (TNBCs) but not in normal MCF-10A cells, induces the dephosphorylation of Cav-1 Tyr-14 by promoting the Ca2+-dependent stimulation of protein tyrosine phosphatase 1B (PTP1B). Consequently, the dephosphorylation of Cav-1 resulted in its disassociation from β-catenin, which enabled the accumulation of β-catenin at cell borders, where it facilitated the formation of cell–cell adhesion complexes via interactions with R-cadherin and desmosomal proteins. Kv11.1 activation-dependent Cav-1 dephosphorylation induced with NS1643 also reduced cell migration and invasion, consistent with its ability to regulate focal adhesion dynamics. Thus, this study sheds light on a novel pharmacological mechanism of promoting Cav-1 dephosphorylation, which may prove to be effective at reducing metastasis and promoting contact inhibition.

Micronutrient Status and Breast Cancer: A Narrative Review

“…Research has shown that the activation of KV 11.1 channels' expression inhibits tumor growth and metastasis onset by reversing the epithelial-mesenchymal transition. In this case, the application of the KV11.1 channel's activator, NS1643, considerably reduced the progression of the tumor [250,251]. Frajese et al pointed out the potential therapeutic effect of combined potassium-ascorbic acid use in patients with breast cancer.…”

Potassium channels: Novel targets for tumor diagnosis and chemoresistance

“…In normal healthy tissues, its expression level is usually low, and it is high in tissues such as leukemia, ovarian cancer(OC), LC, and BC ( 21 ). Activation of Kv11.1 promotes Cav-1 dephosphorylation thereby reducing BC MDA-MB-231 cell migration and invasion ( 22 ). In glioblastoma(GBM) xenografts, high expression of HERG may be associated with the proliferation ( 23 ).…”