Potassium channel-driven bioelectric signalling regulates metastasis in triple-negative breast cancer
Evidence before this study
While it is widely known in the field that bioelectric properties of cancer cells differ from their normal counterparts, we performed a literature search of primary peer-reviewed papers to gather evidence of the impact of potassium ion channel activity on cancer cell invasion and metastasis. Most studies of potassium channels have focused on its role in regulating tumour cell proliferation and cell cycle progression. We explored prior work using PubMed with the following terms: “potassium channel cancer,” “membrane potential cancer,” and “ion channels metastasis.” After determining that potassium channels were indeed known to influence cancer cell migration and that the link to resting membrane potential was largely unknown, we next searched for the clinical relevance of potassium channels and breast cancer. For this, we searched patient mRNA data using cBioPortal, an open-access online cancer database. From this search we determined that overexpression of potassium channels was indeed associated with triple-negative breast cancer.
Added value of this study
Most studies on the role of ions and ion channels focus on individual channels which are upregulated in cancer. Here, we instead focused on the whole cell changes in the bioelectric properties that all ion channels regulate. This removes the burden on finding the most important ion channel regulating these cellular properties and instead focuses on identifying strategies to target the cellular state. Furthermore, previous studies do not investigate the effect of potassium channel overexpression, which we see in triple-negative breast cancer patient tumours. Lastly, there are no published studies dissecting how whole-cell changes in bioelectric properties, which is a defining features of tumour cells, regulates gene expression.
Implications of all the available evidence
Our research demonstrates that alteration of breast cancer cells through overexpression of K+ channels leads to enhanced cell invasion, tumour growth, and metastasis. We also identify a novel Hyperpolarization-driven mechanism of cell migration mediated by cadherin-11 and MAPK signalling. These data suggest that potassium channels are important in driving breast cancer invasion and metastasis, and, coupled with patient data showing potassium channels are upregulated in TNBC tumours, are a viable target for cancer therapies. Our data supports this implication by identifying a novel FDA-approved drug, amiodarone, that can decrease breast cancer cell migration in vitro and metastasis in vivo by targeting the bioelectric state of the cell. Approving new drugs for cancer treatment is expensive (up to 1 billion dollars) and lengthy (at least 10 years). Overall, 310 FDA-approved drugs have been implicated in regulating cancer behaviors, but to be prescribed by clinicians, these drugs would need to undergo additional small scale clinical trials. For this to occur, additional scientific evidence to support a certain class of drugs is necessary to help prioritize what drugs are likely to prove most beneficial to patients. Our data suggest that amiodarone may be a good candidate for further study.
Hyperpolarization of breast tumour cells increases invasion and metastasis and that depolarization of cells can be used to reduce metastatic burden.
Hyperpolarization is a change in a cell's membrane potential that makes it more negative. It is the opposite of a depolarization.
Depolarization is a change within a cell, during which the cell undergoes a shift in electric charge distribution, resulting in less negative charge inside the cell compared to the outside.
Heart cancer is very rare because heart is constantly depolarized like nervous cells. Those are also low in cancer.
Metabolic Modulation of Glioblastoma with Dichloroacetate http://stm.sciencemag.org/content/2/31/31ra34.abstract
Solid tumors, including the aggressive primary brain cancer glioblastoma multiforme, develop resistance to cell death, in part as a result of a switch from mitochondrial oxidative phosphorylation to cytoplasmic glycolysis. This metabolic remodeling is accompanied by mitochondrial hyperpolarization. We tested whether the small-molecule and orphan drug dichloroacetate (DCA) can reverse this cancer-specific metabolic and mitochondrial remodeling in glioblastoma. Freshly isolated glioblastomas from 49 patients showed mitochondrial hyperpolarization, which was rapidly reversed by DCA.
What drugs reverse hyperpolarization?