Potassium channel-driven bioelectric signalling regulates metastasis in triple-negative breast cancer

Abstract

Summary Background There is a critical need to better understand the mechanisms that drive local cell invasion and metastasis to develop new therapeutics targeting metastatic disease. Bioelectricity is an important mediator of cellular processes and changes in the resting membrane potential (RMP) are associated with increased cancer cell invasion. However, whether the RMP can be used to target invading cancer cells is unknown. Methods We employed both genetic and pharmacological manipulation of potassium channel activity and characterized the effects on breast cancer cell migration and invasion in vitro , and metastasis in an animal model of breast cancer. Findings Our data demonstrate that altering the RMP of triple-negative breast cancer (TNBC) cells by manipulating potassium channel expression increases in vitro invasion, in vivo tumour growth and metastasis, and is accompanied by changes in gene expression associated with cell adhesion. Interpretation We describe a novel mechanism for RMP-mediated cell migration involving cadherin-11 and the MAPK pathway. Importantly, we identify a new strategy to target metastatic TNBC in vivo by repurposing an FDA-approved potassium channel blocker. Our results demonstrate that bioelectricity regulates cancer cell invasion and metastasis which could lead to a new class of therapeutics for patients with metastatic disease. Funding This work was supported by the National Institutes of Health (R00-CA207866 to M.J.O.), Tufts University (Start-up funds from the School of Engineering to M.J.O., Tufts Collaborates Award to M.J.O. and M.L.), Allen Discovery centre program (Paul G. Allen Frontiers Group (12,171) to M.L.), and Breast Cancer Alliance Young Investigator Grant to M.J.O, Laidlaw Scholar funding to D.S. M.L. also gratefully acknowledges support of the Barton Family Foundation.

Potassium channels: Novel targets for tumor diagnosis and chemoresistance

“…In addition, the researchers found that Kv1.3 channel blockade was able to lead to phosphorylation of the transcription factor CREB in LUAD A549 cells and play a specific role in cell proliferation, apoptosis and differentiation, thereby affecting the development of lung cancer(LC) cells ( 15 ). Kv1.5 overexpression driving resting membrane potential(RMP) hyperpolarization may alter adhesion and morphology of triple-negative breast cancer(TNBC) cells and increase TNBC cell migration and invasion ( 16 ).…”

Bioelectric Dysregulation in Cancer Initiation, Promotion, and Progression

“…The K + channel EAG has been found to be expressed in 100% of cervical cancer biopsies analyzed and overexpression of EAG in human cells has been shown to increase cell proliferation in culture ( 71 , 72 ). Furthermore, overexpressing K + channels in breast cancer cells has been found to drive cell migration mediated by cadherin-11 and MAPK signaling ( 73 ). Calcium-dependent K + channel K Ca 3.1 also promoted proliferation by directly interacting with ERK1/2 and JNK signaling pathways ( 74 ).…”

Targeting Tumor Microenvironment by Metal Peroxide Nanoparticles in Cancer Therapy

“…Te metal ions released after the degradation are observed to have some signifcant ramifcations, such as excess calcium caused by Ca 2+ ions released from CaO 2 which is thought to cause mitochondrial damage [166,178,179]. Te released Ba 2+ ions produced by the degradation reaction of BaO 2 are known to act as a potassium ion pump suppressor, inhibiting tumor progression [180,181].…”