Voltage-Gated Potassium Channel Kv1.3 as a Target in Therapy of Cancer

Teisseyre, Andrzej; Palko-Łabuz, Anna; Środa-Pomianek, Kamila; Michalak, Krystyna

doi:10.3389/fonc.2019.00933

Cited by 76 publications

(171 citation statements)

References 74 publications

(226 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]. We are targeting BK channel since it has the largest conductance in the potassium channel family.…”

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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“…The different functions of the plasmalemma and mitochondrial Kv1.3 channel necessitated the development of selective inhibitors for mitoKv1.3. Two psoralen derivatives (PAP-1) were developed that accumulate in negatively charged mitochondria due to the lipophilic, positively charged triphenylphosphate (TPP + ) group [72,73]. In PAPTP, the TPP + group is connected by a stable C-C bond.…”

Section: Searching For Specific Drugs Targeting Mitokv13 Channelsmentioning

confidence: 99%

Mitochondrial Potassium Channels as Druggable Targets

et al. 2020

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Mitochondrial potassium channels have been described as important factors in cell pro-life and death phenomena. The activation of mitochondrial potassium channels, such as ATP-regulated or calcium-activated large conductance potassium channels, may have cytoprotective effects in cardiac or neuronal tissue. It has also been shown that inhibition of the mitochondrial Kv1.3 channel may lead to cancer cell death. Hence, in this paper, we examine the concept of the druggability of mitochondrial potassium channels. To what extent are mitochondrial potassium channels an important, novel, and promising drug target in various organs and tissues? The druggability of mitochondrial potassium channels will be discussed within the context of channel molecular identity, the specificity of potassium channel openers and inhibitors, and the unique regulatory properties of mitochondrial potassium channels. Future prospects of the druggability concept of mitochondrial potassium channels will be evaluated in this paper.

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“…It is widely accepted that Kv channels participate in cancer development and progression and their expression has shown to be aberrant in several types of tumor tissue, also in PDAC (Serrano-Novillo et al, 2019;Teisseyre et al, 2019). It has been shown that Kv1.3 is expressed in different human PDAC cell lines, harboring mutation in p53 (Zaccagnino et al, 2017).…”

Section: Kv Channelsmentioning

confidence: 99%

Ion Channel Signature in Healthy Pancreas and Pancreatic Ductal Adenocarcinoma

et al. 2020

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Pancreatic ductal adenocarcinoma (PDAC) is the fourth most common cause of cancerrelated deaths in United States and Europe. It is predicted that PDAC will become the second leading cause of cancer-related deaths during the next decades. The development of PDAC is not well understood, however, studies have shown that dysregulated exocrine pancreatic fluid secretion can contribute to pathologies of exocrine pancreas, including PDAC. The major roles of healthy exocrine pancreatic tissue are secretion of enzymes and bicarbonate rich fluid, where ion channels participate to fine-tune these biological processes. It is well known that ion channels located in the plasma membrane regulate multiple cellular functions and are involved in the communication between extracellular events and intracellular signaling pathways and can function as signal transducers themselves. Hereby, they contribute to maintain resting membrane potential, electrical signaling in excitable cells, and ion homeostasis. Despite their contribution to basic cellular processes, ion channels are also involved in the malignant transformation from a normal to a malignant phenotype. Aberrant expression and activity of ion channels have an impact on essentially all hallmarks of cancer defined as; uncontrolled proliferation, evasion of apoptosis, sustained angiogenesis and promotion of invasion and migration. Research indicates that certain ion channels are involved in the aberrant tumor growth and metastatic processes of PDAC. The purpose of this review is to summarize the important expression, localization, and function of ion channels in normal exocrine pancreatic tissue and how they are involved in PDAC progression and development. As ion channels are suggested to be potential targets of treatment they are furthermore suggested to be biomarkers of different cancers. Therefore, we describe the importance of ion channels in PDAC as markers of diagnosis and clinical factors.

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Voltage-Gated Potassium Channel Kv1.3 as a Target in Therapy of Cancer

Cited by 76 publications

References 74 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

Mitochondrial Potassium Channels as Druggable Targets

Ion Channel Signature in Healthy Pancreas and Pancreatic Ductal Adenocarcinoma

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