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Opening large-conductance potassium channels selectively induced cell death of triple-negative breast cancer.

ABSTRACT: BACKGROUND:Unlike other breast cancer subtypes that may be treated with a variety of hormonal or targeted therapies, there is a need to identify new, effective targets for triple-negative breast cancer (TNBC). It has recently been recognized that membrane potential is depolarized in breast cancer cells. The primary objective of the study is to explore whether hyperpolarization induced by opening potassium channels may provide a new strategy for treatment of TNBC. METHODS:Breast cancer datasets in cBioPortal for cancer genomics was used to search for ion channel gene expression. Immunoblots and immunohistochemistry were used for protein expression in culture cells and in the patient tissues. Electrophysiological patch clamp techniques were used to study properties of BK channels in culture cells. Flow cytometry and fluorescence microscope were used for cell viability and cell cycle studies. Ultrasound imaging was used to study xenograft in female NSG mice. RESULTS:In large datasets of breast cancer patients, we identified a gene, KCNMA1 (encoding for a voltage- and calcium-dependent large-conductance potassium channel, called BK channel), overexpressed in triple-negative breast cancer patients. Although overexpressed, 99% of channels are closed in TNBC cells. Opening BK channels hyperpolarized membrane potential, which induced cell cycle arrest in G2 phase and apoptosis via caspase-3 activation. In a TNBC cell induced xenograft model, treatment with a BK channel opener significantly slowed tumor growth without cardiac toxicity. CONCLUSIONS:Our results support the idea that hyperpolarization induced by opening BK channel in TNBC cells can become a new strategy for development of a targeted therapy in TNBC.

SUBMITTER: Sizemore G

PROVIDER: S-EPMC7318490 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Opening large-conductance potassium channels selectively induced cell death of triple-negative breast cancer.

Sizemore Gina G McLaughlin Sarah S Newman Mackenzie M Brundage Kathleen K Ammer Amanda A Martin Karen K Pugacheva Elena E Coad James J Mattes Malcolm D MD Yu Han-Gang HG

BMC cancer 20200626 1

<h4>Background</h4>Unlike other breast cancer subtypes that may be treated with a variety of hormonal or targeted therapies, there is a need to identify new, effective targets for triple-negative breast cancer (TNBC). It has recently been recognized that membrane potential is depolarized in breast cancer cells. The primary objective of the study is to explore whether hyperpolarization induced by opening potassium channels may provide a new strategy for treatment of TNBC.<h4>Methods</h4>Breast ca ...[more]

PMID: 32586284

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Project description:Large conductance (BK-type) calcium-activated potassium channels utilize alternative splicing and association with accessory beta subunits to tailor BK channel properties to diverse cell types. Two important modulators of BK channel gating are the neuronal-specific beta4 accessory subunit (beta4) and alternative splicing at the stress axis hormone-regulated exon (STREX). Individually, these modulators affect the gating properties of the BK channel as well as its response to phosphorylation. In this study, the combined functional consequences of STREX and the mouse beta4 subunit on mouse BK channel biophysical properties were investigated in transfected HEK 293 cells. Surprisingly, we found that the combined effects of STREX and beta4 are non-additive and even opposite for some properties. At high calcium, beta4 and the STREX individually share properties that promote BK channel opening via slowing of deactivation. However, the combined effects are a speeding of deactivation and a decreased open probability. beta4 also inhibits BK channel opening by a slowing of activation. This effect occurs across calcium concentrations in the absence of STREX, but predominates only at low calcium for STREX containing channels. BK channel responses to phosphorylation status are also altered by the combination of the beta4 subunit and STREX. beta4/STREX channels show a slowing of activation kinetics following dephosphorylation whereas beta4 channels lacking STREX do not. In contrast, beta4 confers a speeding of activation in response to cyclic AMP-dependent phosphorylation in channels lacking STREX, but not in channels containing STREX. These results indicate that the combination of the beta4 subunit and STREX confers non-additive and unique properties to BK channels. Analysis of expression in brain slices suggests that STREX and beta4 mRNA overlap expression in the dentate gyrus of the hippocampus and the cerebellar Purkinje cells, suggesting that these unique properties of BK channels may underlie BK channel gating in these cells.

Dataset Information

Opening large-conductance potassium channels selectively induced cell death of triple-negative breast cancer.

Publications

Opening large-conductance potassium channels selectively induced cell death of triple-negative breast cancer.

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