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

BMC Cancer

Karen Martin¹  Amanda Ammer¹  Sarah McLaughlin¹  Gina Sizemore²  Elena Pugacheva³  Kathleen Brundage⁴  James Coad⁵  Han-Gang Yu⁶  Mackenzie Newman⁶  Malcolm D. Mattes⁷ 

[1] Animal Models & Imaging Facility, Cancer Institute, West Virginia University;Clinical and Translational Sciences Institute, West Virginia University;Department of Biochemistry, Cancer Institute, West Virginia University;Department of Microbiology and Cell Biology, Flow Cytometry Facility, West Virginia University;Department of Pathology, West Virginia University;Department of Physiology & Pharmacology, West Virginia University;Department of Radiation Oncology, Cancer Institute, West Virginia University;

关键词: Potassium channels;    Hyperpolarization;    Triple-negative breast cancer;   

DOI  :  10.1186/s12885-020-07071-1

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown