Nuclear Localization and Functional Characteristics of Voltage-gated Potassium Channel Kv1.3

Jang, Seung‐Ho; Byun, Jun Kyu; Jeon, Won Il; Choi, Seon Young; Park, Jin; Lee, Bo Hyung; Yang, Ji Eun; Park, Jin Bong; O’Grady, Scott M.; Kim, Dae Yong; Ryu, Pan Dong; Joo, Sang Woo; Lee, So Yeong

doi:10.1074/jbc.m114.561324

Cited by 49 publications

(49 citation statements)

References 51 publications

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“…expression of Kv1.3 in mitochondrial and plasma membranes, had already been found in breast cancer MCF-7, prostate cancer PC3, osteosarcoma SAOS-2, melanoma B16F10, Jurkat T cell lymphoma [22,26,27] and pancreas carcinoma [28]. In addition, recent data indicate the presence of Kv1.3 also in cis-Golgi [29] and in the nuclear membrane [30], which is also consistent with the present studies. The function of the cis-Golgi-located channels is unknown, while nuclear Kv1.3 has been suggested to impact on transcription factor activation via regulation of the nuclear membrane potential.…”

Section: Discussionsupporting

confidence: 80%

Targeting the Potassium Channel Kv1.3 Kills Glioblastoma Cells

et al. 2017

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Background/Aims: Glioblastoma (GBM) is one of the most aggressive cancers, counting for a high number of the newly diagnosed patients with central nervous system (CNS) cancers in the United States and Europe. Major features of GBM include aggressive and invasive growth as well as a high resistance to treatment. Kv1.3, a potassium channel of the shaker family, is expressed in the inner mitochondrial membrane of many cancer cells. Inhibition of mitochondrial Kv1.3 was shown to induce apoptosis in several tumor cells at doses that were not lethal for normal cells. Methods: We investigated the expression of Kv1.3 in different glioma cell lines by immunocytochemistry, western blotting and electron microscopy and analyzed the effect of newly synthesized, mitochondria-targeted, Kv1.3 inhibitors on the induction of cell death in these cells. Finally, we performed in vivo studies on glioma bearing mice. Results: Here, we report that Kv1.3 is expressed in mitochondria of human and murine GL261, A172 and LN308 glioma cells. Treatment with the novel Kv1.3 inhibitors PAPTP or PCARBTP as well as with clofazimine induced massive cell death in glioma cells, while Psora-4 and PAP-1 were almost without effect. However, in vivo experiments revealed that the drugs had no effect on orthotopic brain tumors in vivo. Conclusion: These data serve as proof of principle that Kv1.3 inhibitors kills GBM cells, but drugs that act in vivo against glioblastoma must be developed to translate these findings in vivo.

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Section: Discussionsupporting

confidence: 80%

Targeting the Potassium Channel Kv1.3 Kills Glioblastoma Cells

et al. 2017

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“…Interestingly, K V 1.5 was also detected on the nuclei envelope, a cellular structure that is continuous with endoplasmic reticulum (ER) and serves as a site of initial protein synthesis for some membrane proteins. 28, 29 K V 1.4 protein was also detected in VSMCs, however the expression of K V 1.4 protein was lower than that of K V 1.5 and also seemed largely intracellular.…”

Section: Resultsmentioning

confidence: 90%

Contribution of K _V 1.5 Channel to Hydrogen Peroxide–Induced Human Arteriolar Dilation and Its Modulation by Coronary Artery Disease

Nishijima

Cao

Chabowski

et al. 2017

Circulation Research

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Rationale Hydrogen peroxide (H2O2) regulates vascular tone in the human microcirculation under physiological and pathophysiological conditions. It dilates arterioles by activating BKCa channels in subjects with coronary artery disease (CAD), but its mechanisms of action in subjects without CAD (non-CAD) as compared to those with CAD remain unknown. Objective We hypothesize that H2O2-elicited dilation involves different K+ channels in non-CAD versus CAD, resulting in an altered capacity for vasodilation during disease. Methods and Results H2O2 induced endothelium-independent vasodilation in non-CAD adipose arterioles, which was reduced by paxilline, a BKCa channel blocker, and by 4-AP, a KV channel blocker. Assays of mRNA transcripts, protein expression and subcellular localization revealed that KV1.5 is the major KV1 channel expressed in vascular smooth muscle cells (VSMCs) and is abundantly localized on the plasma membrane. The selective KV1.5 blocker DPO-1 and the KV1.3/1.5 blocker Psora-4 reduced H2O2-elicited dilation to a similar extent as 4-AP, but the selective KV1.3 blocker PAP-1 was without effect. In arterioles from CAD subjects, H2O2-induced dilation was significantly reduced and this dilation was inhibited by paxilline but not by 4-AP, DPO-1 or Psora-4. KV1.5 cell membrane localization and DPO-1-sensitive K+ currents were markedly reduced in isolated VSMCs from CAD arterioles, although mRNA or total cellular protein expression were largely unchanged. Conclusions In human arterioles, H2O2-induced dilation is impaired in CAD, which is associated with a transition from a combined BKCa- and KV (KV1.5)-mediated vasodilation toward a BKCa-predominant mechanism of dilation. Loss of KV1.5 vasomotor function may play an important role in microvascular dysfunction in CAD or other vascular diseases.

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“…Kv1.3 was located to the cis-Golgi membranes as well [29] and, recently, to the nuclear membrane [30] where it seems to be involved in regulation of transcription. Expression of the channel in the IMM seems to correlate with that in the PM (e.g.…”

Section: Introductionmentioning

confidence: 99%

Tumor-reducing effect of the clinically used drug clofazimine in a SCID mouse model of pancreatic ductal adenocarcinoma

Zaccagnino¹,

Managò

Leanza

et al. 2016

Oncotarget

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Pancreatic ductal adenocarcinoma (PDAC) represents the most common form of pancreatic cancer with rising incidence in developing countries. Unfortunately, the overall 5-year survival rate is still less than 5%. The most frequent oncogenic mutations in PDAC are loss-of function mutations in p53 and gain-of-function mutations in KRAS. Here we show that clofazimine (Lamprene), a drug already used in the clinic for autoimmune diseases and leprosy, is able to efficiently kill in vitro five different PDAC cell lines harboring p53 mutations. We provide evidence that clofazimine induces apoptosis in PDAC cells with an EC50 in the μM range via its specific inhibitory action on the potassium channel Kv1.3. Intraperitoneal injection of clofazimine resulted in its accumulation in the pancreas of mice 8 hours after administration. Using an orthotopic PDAC xenotransplantation model in SCID beige mouse, we show that clofazimine significantly and strongly reduced the primary tumor weight. Thus, our work identifies clofazimine as a promising therapeutic agent against PDAC and further highlights ion channels as possible oncological targets.

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Nuclear Localization and Functional Characteristics of Voltage-gated Potassium Channel Kv1.3

Abstract: Background: Voltage-gated K ϩ channels are generally known to be located in the plasma membrane.

Cited by 49 publications

References 51 publications

Targeting the Potassium Channel Kv1.3 Kills Glioblastoma Cells

Targeting the Potassium Channel Kv1.3 Kills Glioblastoma Cells

Contribution of K _V 1.5 Channel to Hydrogen Peroxide–Induced Human Arteriolar Dilation and Its Modulation by Coronary Artery Disease

Tumor-reducing effect of the clinically used drug clofazimine in a SCID mouse model of pancreatic ductal adenocarcinoma

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Nuclear Localization and Functional Characteristics of Voltage-gated Potassium Channel Kv1.3

Abstract: Background: Voltage-gated K ϩ channels are generally known to be located in the plasma membrane.

Cited by 49 publications

References 51 publications

Targeting the Potassium Channel Kv1.3 Kills Glioblastoma Cells

Targeting the Potassium Channel Kv1.3 Kills Glioblastoma Cells

Contribution of K V 1.5 Channel to Hydrogen Peroxide–Induced Human Arteriolar Dilation and Its Modulation by Coronary Artery Disease

Tumor-reducing effect of the clinically used drug clofazimine in a SCID mouse model of pancreatic ductal adenocarcinoma

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Contribution of K _V 1.5 Channel to Hydrogen Peroxide–Induced Human Arteriolar Dilation and Its Modulation by Coronary Artery Disease