Ion Channel Regulation by Sex Steroid Hormones and Vitamin D in Cancer: A Potential Opportunity for Cancer Diagnosis and Therapy

Restrepo-Angulo, Iván; Bañuelos, Cecilia; Camacho, Javier

doi:10.3389/fphar.2020.00152

Cited by 23 publications

(14 citation statements)

References 99 publications

(122 reference statements)

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“…Recently, voltage-gated potassium channels have attracted cancer investigators for their potential as targets in cancer therapy [51,52]. Kv1.3 has gained particular attention due to its low expression in the heart, while overexpressed in cancer [53,54].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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“…These genes are involved in synaptic transmission, cholinergic (GO:0007271, FDR adjust p value = 3.54E-19), and acetylcholine receptor signaling pathways (GO:0095500, FDR adjust p value = 1.91E-10) of Radix Sophorae Flavescentis in HCGSC. For the remaining GO-BP terms of Rhizoma Heterosmilacis in HCGSC, some steroid hormones, such as vitamin D, may have anticancer properties, while others may favor cancer progression, including estrogens and androgens ( Restrepo-Angulo et al, 2020 ), which are related to regulation of steroid metabolic processes (GO:0019218, FDR adjusted p value = 2.49E-13).…”

Section: Resultsmentioning

confidence: 99%

A System Pharmacology Model for Decoding the Synergistic Mechanisms of Compound Kushen Injection in Treating Breast Cancer

Wang

Chen

et al. 2021

Front. Pharmacol.

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Breast cancer (BC) is one of the most common malignant tumors among women worldwide and can be treated using various methods; however, side effects of these treatments cannot be ignored. Increasing evidence indicates that compound kushen injection (CKI) can be used to treat BC. However, traditional Chinese medicine (TCM) is characterized by “multi-components” and “multi-targets”, which make it challenging to clarify the potential therapeutic mechanisms of CKI on BC. Herein, we designed a novel system pharmacology strategy using differentially expressed gene analysis, pharmacokinetics synthesis screening, target identification, network analysis, and docking validation to construct the synergy contribution degree (SCD) and therapeutic response index (TRI) model to capture the critical components responding to synergistic mechanisms of CKI in BC. Through our designed mathematical models, we defined 24 components as a high contribution group of synergistic components (HCGSC) from 113 potentially active components of CKI based on ADME parameters. Pathway enrichment analysis of HCGSC targets indicated that Rhizoma Heterosmilacis and Radix Sophorae Flavescentis could synergistically target the PI3K-Akt signaling pathway and the cAMP signaling pathway to treat BC. Additionally, TRI analysis showed that the average affinity of HCGSC and targets involved in the key pathways reached -6.47 kcal/mmol, while in vitro experiments proved that two of the three high TRI-scored components in the HCGSC showed significant inhibitory effects on breast cancer cell proliferation and migration. These results demonstrate the accuracy and reliability of the proposed strategy.

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“…Steroid hormones (SSH), including calcitriol, can regulate potassium ion channels via direct binding to a channel protein or to an auxiliary protein that regulates the gating properties of the channel. Another possibility is indirect regulation via signaling pathways initiated from SSH receptors in the plasma membrane or cytosol including classic genomic transcriptional pathways or by changing the properties of the lipid bilayer in which the channels are located [58][59][60]. So far, there is no literature data on the influence of calcitriol on the activity of the potassium channels from the inner mitochondrial membrane, and in the case of the cell membrane, this knowledge is reduced to a few studies.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial potassium channels: A novel calcitriol target

et al. 2022

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Background Calcitriol (an active metabolite of vitamin D) modulates the expression of hundreds of human genes by activation of the vitamin D nuclear receptor (VDR). However, VDR-mediated transcriptional modulation does not fully explain various phenotypic effects of calcitriol. Recently a fast non-genomic response to vitamin D has been described, and it seems that mitochondria are one of the targets of calcitriol. These non-classical calcitriol targets open up a new area of research with potential clinical applications. The goal of our study was to ascertain whether calcitriol can modulate mitochondrial function through regulation of the potassium channels present in the inner mitochondrial membrane. Methods The effects of calcitriol on the potassium ion current were measured using the patch-clamp method modified for the inner mitochondrial membrane. Molecular docking experiments were conducted in the Autodock4 program. Additionally, changes in gene expression were investigated by qPCR, and transcription factor binding sites were analyzed in the CiiiDER program. Results For the first time, our results indicate that calcitriol directly affects the activity of the mitochondrial large-conductance Ca2+-regulated potassium channel (mitoBKCa) from the human astrocytoma (U-87 MG) cell line but not the mitochondrial calcium-independent two-pore domain potassium channel (mitoTASK-3) from human keratinocytes (HaCaT). The open probability of the mitoBKCa channel in high calcium conditions decreased after calcitriol treatment and the opposite effect was observed in low calcium conditions. Moreover, using the AutoDock4 program we predicted the binding poses of calcitriol to the calcium-bound BKCa channel and identified amino acids interacting with the calcitriol molecule. Additionally, we found that calcitriol influences the expression of genes encoding potassium channels. Such a dual, genomic and non-genomic action explains the pleiotropic activity of calcitriol. Conclusions Calcitriol can regulate the mitochondrial large-conductance calcium-regulated potassium channel. Our data open a new chapter in the study of non-genomic responses to vitamin D with potential implications for mitochondrial bioenergetics and cytoprotective mechanisms.

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Ion Channel Regulation by Sex Steroid Hormones and Vitamin D in Cancer: A Potential Opportunity for Cancer Diagnosis and Therapy

Cited by 23 publications

References 99 publications

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

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

A System Pharmacology Model for Decoding the Synergistic Mechanisms of Compound Kushen Injection in Treating Breast Cancer

Mitochondrial potassium channels: A novel calcitriol target

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