Expression and effects of modulation of the K2P potassium channels TREK-1 (KCNK2) and TREK-2 (KCNK10) in the normal human ovary and epithelial ovarian cancer

Innamaa, Anni; Jackson, Leigh; Asher, Viren; Schalkwyk, Gerhard van; Warren, Averil Y.; Keightley, Angela M.; Hay, Daniel; Bali, Anish; Sowter, Heidi M.; Khan, Raheela

doi:10.1007/s12094-013-1022-4

Cited by 42 publications

(35 citation statements)

References 27 publications

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“…4D–H). Specific blockers of two-pore K + channels known to be overexpressed in SKOV-3 cells 17, 18 , such as 20 µM curcumin, 100 µM L-methionine, 100 µM TPenA (a TREK-1 and TREK-2 blocker), and 20 µM methanandamide (a TASK-3 blocker), showed only small inhibitory effects (ranging from 12 to 26%) on the K + current elicited by ATP (or UTP; n = 22) that were not significant when compared with the amplitude of control currents (Fig. 4D).…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, outward current responses elicited by ATP were potently blocked by TEA + or 4-AP, two unspecific K + channel blockers. Treatment of cells with more specific drugs indicated that the main pathway involved did not correspond to activation of two-pore K + channels (TASK-3, TREK-1 and TREK-2), or to Ca 2+ -dependent K + channels sensitive to apamin, some of which are proposed to be related to the cancer process in SKOV-3 cells 17, 18 . However, TRAM-34, a specific drug for Ca 2+ -dependent K + channels of intermediate-conductance corresponding to the K Ca 3.1 subtype, proved to be an effective blocker of the SKOV-3 response.…”

Section: Discussionmentioning

confidence: 99%

“…ATP application generates in SKOV-3 an increase in the intracellular Ca 2+ concentration ([Ca 2+ ] i ) via its release through P2 receptor stimulation 16 , and a similar [Ca 2+ ] i increase is evoked by histaminergic signaling activation; the effect of this [Ca 2+ ] i increase on membrane conductance, however, remains to be explored. On the other hand, the expression and function of K + channels correlate with the cancer progression in SKOV-3 cells, as some specific K + -channel subtypes, such as two-pore K + channels, are upregulated 17, 18 .…”

Section: Introductionmentioning

confidence: 99%

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Kca3.1 Activation Via P2y2 Purinergic Receptors Promotes Human Ovarian Cancer Cell (Skov-3) Migration

Robles-Martínez

Garay

Martel-Gallegos

et al. 2017

Sci Rep

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Disorders in cell signaling mediated by ATP or histamine, activating specific membrane receptors, have been frequently associated with tumorigenesis. Among the elements of response to purinergic (and histaminergic) signaling, ion channel activation controls essential cellular processes in cancer, such as cell proliferation, motility, and death. Here, we studied the effects that ATP had on electrical properties of human ovarian adenocarcinoma cells named SKOV-3. ATP caused increase in intracellular Ca2+ concentration ([Ca2+]i) and, concurrently, it evoked a complex electrical response with a conspicuous outward component. This current was generated through P2Y2 receptor activation and opening of K+ channels, KCa3.1, as indicated by electrophysiological and pharmacological analysis, as well as by immunodetection and specific silencing of P2Y2 or KCa3.1 gene by esiRNA transfection. Low µM ATP concentration increased SKOV-3 cell migration, which was strongly inhibited by KCa3.1 channel blockers and by esiRNA-generated P2Y2 or KCa3.1 downregulation. Finally, in human ovarian tumors, the P2Y2 and KCa3.1 proteins are expressed and co-localized in neoplastic cells. Thus, stimulation of P2Y2 receptors expressed in SKOV-3 cells promotes motility through KCa3.1 activation. Since P2Y2 and KCa3.1 are co-expressed in primary tumors, our findings suggest that they may play a role in cancer progression.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Kca3.1 Activation Via P2y2 Purinergic Receptors Promotes Human Ovarian Cancer Cell (Skov-3) Migration

Robles-Martínez

Garay

Martel-Gallegos

et al. 2017

Sci Rep

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“…K2P channels and pH-sensitive GPCRs have not been studied extensively in brain tumor tissue, though their roles in other cancers have been elucidated (Sin et al, 2004; Innamaa et al, 2013). The K2P members TASK-1 and TASK-3, pH-sensitive background K + channels, have functional expression in human medulloblastoma cells (Ernest et al, 2010) and have been functionally implicated in glioma cell survival (Meuth et al, 2008).…”

Section: Ion Channel Signalingmentioning

confidence: 99%

Involvement of tumor acidification in brain cancer pathophysiology

Honasoge

Sontheimer

2013

Front. Physiol.

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Gliomas, primary brain cancers, are characterized by remarkable invasiveness and fast growth. While they share many qualities with other solid tumors, gliomas have developed special mechanisms to convert the cramped brain space and other limitations afforded by the privileged central nervous system into pathophysiological advantages. In this review we discuss gliomas and other primary brain cancers in the context of acid-base regulation and interstitial acidification; namely, how the altered proton (H+) content surrounding these brain tumors influences tumor development in both autocrine and paracrine manners. As proton movement is directly coupled to movement of other ions, pH serves as both a regulator of cell activity as well as an indirect readout of other cellular functions. In the case of brain tumors, these processes result in pathophysiology unique to the central nervous system. We will highlight what is known about pH-sensitive processes in brain tumors in addition to gleaning insight from other solid tumors.

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“…TREK1 was also reported as a novel tumor marker in prostate cancer cells [8]. More recently, the presence of the TREK2 channel was reported in normal human ovaries and ovarian cancer [9]. Nonetheless, sufficient data on TREK2 in cancer cells is limited.…”

Section: Introductionmentioning

confidence: 99%

The TREK2 Channel Is Involved in the Proliferation of 253J Cell, a Human Bladder Carcinoma Cell

Park

Han

Jang

et al. 2013

Korean J Physiol Pharmacol

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Bladder cancer is the seventh most common cancer in men that smoke, and the incidence of disease increases with age. The mechanism of occurrence has not yet been established. Potassium channels have been linked with cell proliferation. Some two-pore domain K+ channels (K2P), such as TASK3 and TREK1, have recently been shown to be overexpressed in cancer cells. Here we focused on the relationship between cell growth and the mechanosensitive K2P channel, TREK2, in the human bladder cancer cell line, 253J. We confirmed that TREK2 was expressed in bladder cancer cell lines by Western blot and quantitative real-time PCR. Using the patch-clamp technique, the mechanosensitive TREK2 channel was recorded in the presence of symmetrical 150 mM KCl solutions. In 253J cells, the TREK2 channel was activated by polyunsaturated fatty acids, intracellular acidosis at -60 mV and mechanical stretch at -40 mV or 40 mV. Furthermore, small interfering RNA (siRNA)-mediated TREK2 knockdown resulted in a slight depolarization from -19.9 mV±0.8 (n=116) to -8.5 mV±1.4 (n=74) and decreased proliferation of 253J cells, compared to negative control siRNA. 253J cells treated with TREK2 siRNA showed a significant increase in the expression of cell cycle boundary proteins p21 and p53 and also a remarkable decrease in protein expression of cyclins D1 and D3. Taken together, the TREK2 channel is present in bladder cancer cell lines and may, at least in part, contribute to cell cycle-dependent growth.

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Expression and effects of modulation of the K2P potassium channels TREK-1 (KCNK2) and TREK-2 (KCNK10) in the normal human ovary and epithelial ovarian cancer

Abstract: TREK-1 and -2 are expressed in normal ovaries and ovarian cancer. TREK-1 modulators have a significant effect on cell proliferation and apoptosis. We propose investigation of the therapeutic potential of TREK-1 blockers is warranted.

Cited by 42 publications

References 27 publications

Kca3.1 Activation Via P2y2 Purinergic Receptors Promotes Human Ovarian Cancer Cell (Skov-3) Migration

Kca3.1 Activation Via P2y2 Purinergic Receptors Promotes Human Ovarian Cancer Cell (Skov-3) Migration

Involvement of tumor acidification in brain cancer pathophysiology

The TREK2 Channel Is Involved in the Proliferation of 253J Cell, a Human Bladder Carcinoma Cell

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