Expression of ether à go-go potassium channels in human gliomas

Patt, Stephan; Preußat, Katja; Beetz, Christian; Kraft, Robert A.; Schrey, M.P.; Kalff, Rolf; Schönherr, Kristina; Heinemann, Stefan H.

doi:10.1016/j.neulet.2004.07.001

Cited by 65 publications

(49 citation statements)

References 18 publications

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“…The expression of the herg1 gene in human glial tumours has also been recently reported by Patt et al (2004). These authors, however, found that the transcript expression was lower in highgrade and higher in low-grade gliomas, especially in the control.…”

Section: Discussionsupporting

confidence: 52%

“…Preliminarily, we examined the expression of Kir 2.1, herg1, helk2 and heag transcripts in both cell lines. hEAG was included in the screen because it is expressed in human primary gliomas (Patt et al, 2004), and because hERG channel inhibitors also block hEAG currents at high concentrations (Gessner and Heinemann, 2003;Gessner et al, 2004).…”

Section: Herg Inhibition Reduces Vegf Secretion In Glioblastoma Celmentioning

confidence: 99%

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hERG1 channels are overexpressed in glioblastoma multiforme and modulate VEGF secretion in glioblastoma cell lines

et al. 2005

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Recent studies have led to considerable advancement in our understanding of the molecular mechanisms that underlie the relentless cell growth and invasiveness of human gliomas. Partial understanding of these mechanisms has (1) improved the classification for gliomas, by identifying prognostic subgroups, and (2) pointed to novel potential therapeutic targets. Some classes of ion channels have turned out to be involved in the pathogenesis and malignancy of gliomas. We studied the expression and properties of K þ channels in primary cultures obtained from surgical specimens: human ether a gò-gò related (hERG)1 voltage-dependent K þ channels, which have been found to be overexpressed in various human cancers, and human ether a gò-gò-like 2 channels, that share many of hERG1's biophysical features. The expression pattern of these two channels was compared to that of the classical inward rectifying K þ channels, IRK, that are widely expressed in astrocytic cells and classically considered a marker of astrocytic differentiation. In our study, hERG1 was found to be specifically overexpressed in high-grade astrocytomas, that is, glioblastoma multiforme (GBM). In addition, we present evidence that, in GBM cell lines, hERG1 channel activity actively contributes to malignancy by promoting vascular endothelial growth factor secretion, thus stimulating the neoangiogenesis typical of high-grade gliomas. Our data provide important confirmation for studies proposing the hERG1 channel as a molecular marker of tumour progression and a possible target for novel anticancer therapies.

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Section: Discussionsupporting

confidence: 52%

Section: Herg Inhibition Reduces Vegf Secretion In Glioblastoma Celmentioning

confidence: 99%

hERG1 channels are overexpressed in glioblastoma multiforme and modulate VEGF secretion in glioblastoma cell lines

et al. 2005

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“…The overexpression of hERG1 channels has been reported in a variety of primary tumors, including prolactin-secreting adenoma [28], endometrial cancer [29], colorectal cancers [30], esophageal cancer [31], glioblastoma [32], glioma [33], and gastric cancer cells [34]. Cherubini et al [29], who first demonstrated the presence of hERG1 channels in primary human neoplasia, claimed that herg mRNA and hERG1 protein were aberrantly expressed in endometrial cancer, and electrophysiological experiments confirmed the presence of functioning hERG1 channels on the plasma membrane of tumor cells.…”

Section: Discussionmentioning

confidence: 99%

“…Investigations have indicated that the hERG1 channel is expressed in several tumor cell lines from different histogenesis and have a critical role in the cell cycle progress, proliferation [16][17][18][19][20][21][22][23][24][25], and adaptation [26,27]. The hERG1 channel has also been found to be more frequently expressed in a variety of primary tumors [28][29][30][31][32][33][34]. It has also been hypothesized that hERG1 marks an early step for cancer development [31] and exerts a regulatory role on the modulation of cell invasiveness [30].…”

Section: Introductionmentioning

confidence: 99%

Prognostic Significance of hERG1 Expression in Gastric Cancer

et al. 2009

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Previous studies have demonstrated that human ether-à-go-go-related potassium channel (hERG1) is highly expressed in many tumor cell lines, as well as in primary human cancers, and, hence, have a critical role in cell cycle progress and proliferation. In this study, hERG1 expression was investigated in gastric cancer by immunohistochemistry and/or reverse transcription polymerase chain reaction (RT-PCR). It was discovered that hERG1, which was negatively expressed in surrounding non-tumor tissues, switched to aberrantly positive expression in gastric cancer. Statistically, there were significant differences in hERG1 protein expression according to factors such as serosal invasion, venous invasion, lymph node metastases, other organ metastases, and stage. The mean survival time for the hERG1-positive expression group was significantly shorter than the negative group, the survival rates for the positive group were significantly lower than the negative group, and hERG1 expression was found to be an independent prognostic factor. In summary, hERG1 channel was proved to be a potential biomarker for gastric cancer invasion and survival.

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“…Thus, there is little evidence to suggest that EAG regulates proliferation in normal tissues at present. However, abnormally expressed EAG may have a role in proliferation and transformation given that human EAG has been suggested to have an oncogenic potential and EAG appears abnormally expressed in several tumor cell lines (13,14,33).…”

Section: Discussionmentioning

confidence: 99%

A voltage-driven switch for ion-independent signaling by ether-à-go-go K ⁺ channels

Hegle

Marble

Wilson

2006

Proc. Natl. Acad. Sci. U.S.A.

136

107

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Voltage-gated channels maintain cellular resting potentials and generate neuronal action potentials by regulating ion flux. Here, we show that Ether-à -go-go (EAG) K ؉ channels also regulate intracellular signaling pathways by a mechanism that is independent of ion flux and depends on the position of the voltage sensor. Regulation of intracellular signaling was initially inferred from changes in proliferation. Specifically, transfection of NIH 3T3 fibroblasts or C2C12 myoblasts with either wild-type or nonconducting (F456A) eag resulted in dramatic increases in cell density and BrdUrd incorporation over vector-and Shaker-transfected controls. The effect of EAG was independent of serum and unaffected by changes in extracellular calcium. Inhibitors of p38 mitogen-activated protein (MAP) kinases, but not p44͞42 MAP kinases (extracellular signal-regulated kinases), blocked the proliferation induced by nonconducting EAG in serum-free media, and EAG increased p38 MAP kinase activity. Importantly, mutations that increased the proportion of channels in the open state inhibited EAG-induced proliferation, and this effect could not be explained by changes in the surface expression of EAG. These results indicate that channel conformation is a switch for the signaling activity of EAG and suggest an alternative mechanism for linking channel activity to the activity of intracellular messengers, a role that previously has been ascribed only to channels that regulate calcium influx.intracellular messenger ͉ mitogen-activated protein kinase ͉ neuromodulation ͉ proliferation ͉ gating V oltage-gated ion channels generate neuronal action potentials, the primary units of information transfer in the brain, by regulating ion f lux (1). Effects of ion channels on synaptic connectivity, transmitter release, plasticity, and other cellular processes are generally assumed to be a secondary consequence of ion f lux. Specifically, changes in membrane potential and action potentials alter Ca 2ϩ inf lux, and Ca 2ϩ regulates multiple intracellular signaling pathways (2-7). Several recent studies, however, have indicated that some voltagegated ion channels are bifunctional proteins (5, 8 -11). These studies show that voltage-gated channels can contribute to transcriptional regulation, protein scaffolding, cell adhesion, and intracellular signaling, and the effects appear largely independent of ion conduction. Recent studies of Ether-á-go-go [EAG (KCNH1)] voltagedependent K ϩ channels suggest that EAG may also be bifunctional. First, a region of Drosophila EAG with similarity to the autoinhibitory domain of Ca 2ϩ ͞calmodulin-dependent protein kinase II can associate with activated, Ca 2ϩ ͞calmodulin-bound Ca 2ϩ ͞calmodulin-dependent protein kinase II. In vitro assays indicate that, once Ca 2ϩ levels decline, EAG-bound kinase retains 5-10% of its maximum Ca 2ϩ -stimulated activity (12). Second, human EAG has been implicated in cell-cycle regulation and cancer: transfection can induce oncogenic transformation, EAG is present in some cancer cell line...

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Expression of ether à go-go potassium channels in human gliomas

Cited by 65 publications

References 18 publications

hERG1 channels are overexpressed in glioblastoma multiforme and modulate VEGF secretion in glioblastoma cell lines

hERG1 channels are overexpressed in glioblastoma multiforme and modulate VEGF secretion in glioblastoma cell lines

Prognostic Significance of hERG1 Expression in Gastric Cancer

A voltage-driven switch for ion-independent signaling by ether-à-go-go K ⁺ channels

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Expression of ether à go-go potassium channels in human gliomas

Cited by 65 publications

References 18 publications

hERG1 channels are overexpressed in glioblastoma multiforme and modulate VEGF secretion in glioblastoma cell lines

hERG1 channels are overexpressed in glioblastoma multiforme and modulate VEGF secretion in glioblastoma cell lines

Prognostic Significance of hERG1 Expression in Gastric Cancer

A voltage-driven switch for ion-independent signaling by ether-à-go-go K + channels

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A voltage-driven switch for ion-independent signaling by ether-à-go-go K ⁺ channels