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Research article
Opening Large-Conductance Potassium Channels Selectively Induced Cell Death of Triple-Negative Breast Cancer
Han-Gang Yu
West Virginia University
Corresponding Author
ORCiD: https://orcid.org/0000-0001-6838-8310
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published version at BMC Cancer.
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.
Keywords
potassium channels, hyperpolarization, triple-negative breast cancer
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CURRENT STATUS: Published
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Posted 13 Jun, 2020
No comments provided
Editorial decision: Minor revision
On 08 Jun, 2020
Editor assigned
On 05 Jun, 2020
Submission checks complete
On 04 Jun, 2020
Editor invited
On 04 Jun, 2020
No comments provided
Editorial decision: Major revision
On 27 May, 2020
Review #2 received
Received 21 May, 2020
Reviewer #2 agreed
On 14 May, 2020
Review #1 received
Received 04 Apr, 2020
Reviewers invited
Invitations sent on 25 Mar, 2020
Reviewer #1 agreed
On 25 Mar, 2020
Editor assigned
On 19 Mar, 2020
Submission checks complete
On 18 Mar, 2020
Editor invited
On 18 Mar, 2020
No comments provided
Editorial decision: Major revision
On 16 Mar, 2020
Review #2 received
Received 12 Mar, 2020
Reviewer #2 agreed
On 01 Mar, 2020
Review #1 received
Received 27 Feb, 2020
Reviewer #1 agreed
On 17 Feb, 2020
Reviewers invited
Invitations sent on 05 Feb, 2020
Editor assigned
On 24 Jan, 2020
First submitted
On 23 Jan, 2020
Submission checks complete
On 23 Jan, 2020
Editor invited
On 23 Jan, 2020
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This preprint is under consideration at BMC Cancer. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research article
Opening Large-Conductance Potassium Channels Selectively Induced Cell Death of Triple-Negative Breast Cancer
Han-Gang Yu
West Virginia University
Corresponding Author
ORCiD: https://orcid.org/0000-0001-6838-8310
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Published
Version 4
Posted 13 Jun, 2020
No comments provided
Editorial decision: Minor revision
On 08 Jun, 2020
Editor assigned
On 05 Jun, 2020
Submission checks complete
On 04 Jun, 2020
Editor invited
On 04 Jun, 2020
No comments provided
Editorial decision: Major revision
On 27 May, 2020
Review #2 received
Received 21 May, 2020
Reviewer #2 agreed
On 14 May, 2020
Review #1 received
Received 04 Apr, 2020
Reviewers invited
Invitations sent on 25 Mar, 2020
Reviewer #1 agreed
On 25 Mar, 2020
Editor assigned
On 19 Mar, 2020
Submission checks complete
On 18 Mar, 2020
Editor invited
On 18 Mar, 2020
No comments provided
Editorial decision: Major revision
On 16 Mar, 2020
Review #2 received
Received 12 Mar, 2020
Reviewer #2 agreed
On 01 Mar, 2020
Review #1 received
Received 27 Feb, 2020
Reviewer #1 agreed
On 17 Feb, 2020
Reviewers invited
Invitations sent on 05 Feb, 2020
Editor assigned
On 24 Jan, 2020
First submitted
On 23 Jan, 2020
Submission checks complete
On 23 Jan, 2020
Editor invited
On 23 Jan, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published version at BMC Cancer.
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.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7