Altered expression of KCNK9 in colorectal cancers

Kim, Chang Jae; Cho, Yong Gu; Jeong, Seong Whan; Kim, Young Sil; Kim, Su Young; Nam, Suk Woo; Lee, Sug Hyung; Yoo, Nam Jin; Lee, Jung Young; Park, Won Sang

doi:10.1111/j.1600-0463.2004.apm1120905.x

Cited by 58 publications

(42 citation statements)

References 24 publications

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“…These reports, however, raise serious doubts and questions, because of the inherently problematic nature of the immunodetection of native channel proteins. Up to 50% of the colorectal cancer cases displayed moderate or high immunoreactivity, but TASK-3 expression did not correlate with the stage of the disease and the protein localized mainly to the cytoplasm (160). Similarly, TASK-3 immunoreactivity was diffusely distributed in the cytoplasm with some perinuclear condensation in gastric carcinoma cells, and the level of expression did not differ significantly from the normal gastric mucosa (177).…”

Section: Apoptosis and Oncogenesismentioning

confidence: 81%

Molecular Background of Leak K⁺Currents: Two-Pore Domain Potassium Channels

Enyedi

Czirják

2010

Physiological Reviews

777

769

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Two-pore domain K+ (K2P) channels give rise to leak (also called background) K+ currents. The well-known role of background K+ currents is to stabilize the negative resting membrane potential and counterbalance depolarization. However, it has become apparent in the past decade (during the detailed examination of the cloned and corresponding native K2P channel types) that this primary hyperpolarizing action is not performed passively. The K2P channels are regulated by a wide variety of voltage-independent factors. Basic physicochemical parameters (e.g., pH, temperature, membrane stretch) and also several intracellular signaling pathways substantially and specifically modulate the different members of the six K2P channel subfamilies (TWIK, TREK, TASK, TALK, THIK, and TRESK). The deep implication in diverse physiological processes, the circumscribed expression pattern of the different channels, and the interesting pharmacological profile brought the K2P channel family into the spotlight. In this review, we focus on the physiological roles of K2P channels in the most extensively investigated cell types, with special emphasis on the molecular mechanisms of channel regulation.

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Section: Apoptosis and Oncogenesismentioning

confidence: 81%

Molecular Background of Leak K⁺Currents: Two-Pore Domain Potassium Channels

Enyedi

Czirják

2010

Physiological Reviews

777

769

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“…Some types of K + channels, such as voltage-gated Kv1.3 channel, voltage-gated HERG channel, and KCNK9 channel, have been reported to be expressed at extremely higher levels in colonic carcinoma specimens than in normal colon tissues [17][18][19]. Furthermore, increased mRNA levels of voltage-gated Cav1.2 Ca 2+ channels and Ca 2+ -conducting channels (TRPM8) have been reported in colorectal adenocarcinoma [20,21].…”

Section: Discussionmentioning

confidence: 99%

Furosemide, a Blocker of Na+/K+/2Cl− Cotransporter, Diminishes Proliferation of Poorly Differentiated Human Gastric Cancer Cells by Affecting G0/G1 State

et al. 2006

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Furosemide, a blocker of Na + /K + /2Cl -cotransporter (NKCC), is often used as a diuretic to improve edema, ascites, and pleural effusion of patients with cancers. The aim of the present study was to investigate whether an NKCC blocker affects cancer cell growth. If so, we would clarify the mechanism of this action. We found that poorly differentiated gastric adenocarcinoma cells (MKN45) expressed the mRNA of NKCC1 three times higher than moderately differentiated ones (MKN28) and that the NKCC in MKN45 showed higher activity than that in MKN28. A cell proliferation assay indicates that furosemide significantly inhibited cell growth in MKN45 cells, but not in MKN28 cells. Using flow cytometrical analysis, we found that the exposure to furosemide brought MKN45 cells to spend more time at the G 0 /G 1 phase, but not MKN28 cells. Based on these observations, we indicate that furosemide diminishes cell growth by delaying the G 1 -S phase progression in poorly differentiated gastric adenocarcinoma cells, which show high expression and activity of NKCC, but not in moderately differentiated gastric adenocarcinoma cells with low expression and NKCC activity.Key words: gastric cancer cell, Na + /K + /2Cl -cotransporter (NKCC), furosemide, cell cycle, cell proliferation.In the past two decades, many researchers have reported the characteristics of ion channels/transporters in various types of cells, including cancer cells. Several types of K + , Ca 2+ , and Cl -channels have been identified in colorectal, breast, lung, and prostate cancer cells [1,2]. Some studies indicate that the transepithelial ion transport plays an important role in cell apoptosis [3,4]. Particularly, the modulation of Cl -transport via Cl -channel, K + /Cl -cotransporter (KCC), and Na + /K + /2Cl -cotransporter (NKCC) occurs in cell proliferation [5][6][7]. However, it is unknown whether NKCC affects the proliferation of cancer cells. In the treatment of patients with terminal stage cancers, however, furosemide (an NKCC blocker, a loop diuretic) is often used as a diuretic to keep urine output and to improve edema, ascites, or pleural effusion. Therefore we performed the present study to clarify the effect of furosemide on the proliferation of cancer cells.In the present study, we used two human gastric cancer cell lines, MKN28 and MKN45, which were established from moderately and poorly differentiated adenocarcinoma, respectively [8]. We determined the mRNA and functional expression levels of the NKCC and investigated the inhibitory effect of an NKCC blocker, furosemide, on the proliferation in these two cancer cell lines. We found that mRNA and the functional expression levels of NKCC were both higher in MKN45 than in MKN28 cells. Furthermore, furosemide diminished the cell proliferation, delaying the G 1 -S phase progression in MKN45 cells, but not in MKN28 cells. MATERIALS AND METHODSCell culture. The moderately differentiated human gastric adenocarcinoma cell line, MKN28, and the poorly differentiated human gastric adenocarcinoma cel...

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“…Several potassium channels have been implicated in cancer. For example, the two-pore potassium channel TASK-3 (KCNK9) gene amplification has been detected in breast, lung, and colorectal cancers, and its ectopic expression enhances tumorigenicity in nontransformed cells (Mu et al 2003;Kim et al 2004). Selective up-regulation of HERG in several human neoplasms, but not their normal tissue counterparts, has been reported, and pharmacological inhibition of the HERG channel is efficacious in reducing tumor cell proliferation in primary leukemic cells (Pillozzi et al 2002;Jehle et al 2011).…”

Section: Discussionmentioning

confidence: 99%

Voltage-gated potassium channel EAG2 controls mitotic entry and tumor growth in medulloblastoma via regulating cell volume dynamics

et al. 2012

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Medulloblastoma (MB) is the most common pediatric CNS malignancy. We identify EAG2 as an overexpressed potassium channel in MBs across different molecular and histological subgroups. EAG2 knockdown not only impairs MB cell growth in vitro, but also reduces tumor burden in vivo and enhances survival in xenograft studies. Mechanistically, we demonstrate that EAG2 protein is confined intracellularly during interphase but is enriched in the plasma membrane during late G2 phase and mitosis. Disruption of EAG2 expression results in G2 arrest and mitotic catastrophe associated with failure of premitotic cytoplasmic condensation. While the tumor suppression function of EAG2 knockdown is independent of p53 activation, DNA damage checkpoint activation, or changes in the AKT pathway, this defective cell volume control is specifically associated with hyperactivation of the p38 MAPK pathway. Inhibition of the p38 pathway significantly rescues the growth defect and G2 arrest. Strikingly, ectopic membrane expression of EAG2 in cells at interphase results in cell volume reduction and mitotic-like morphology. Our study establishes the functional significance of EAG2 in promoting MB tumor progression via regulating cell volume dynamics, the perturbation of which activates the tumor suppressor p38 MAPK pathway, and provides clinical relevance for targeting this ion channel in human MBs.

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Altered expression of KCNK9 in colorectal cancers

Cited by 58 publications

References 24 publications

Molecular Background of Leak K⁺Currents: Two-Pore Domain Potassium Channels

Molecular Background of Leak K⁺Currents: Two-Pore Domain Potassium Channels

Furosemide, a Blocker of Na+/K+/2Cl− Cotransporter, Diminishes Proliferation of Poorly Differentiated Human Gastric Cancer Cells by Affecting G0/G1 State

Voltage-gated potassium channel EAG2 controls mitotic entry and tumor growth in medulloblastoma via regulating cell volume dynamics

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Altered expression of KCNK9 in colorectal cancers

Cited by 58 publications

References 24 publications

Molecular Background of Leak K+Currents: Two-Pore Domain Potassium Channels

Molecular Background of Leak K+Currents: Two-Pore Domain Potassium Channels

Furosemide, a Blocker of Na+/K+/2Cl− Cotransporter, Diminishes Proliferation of Poorly Differentiated Human Gastric Cancer Cells by Affecting G0/G1 State

Voltage-gated potassium channel EAG2 controls mitotic entry and tumor growth in medulloblastoma via regulating cell volume dynamics

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Molecular Background of Leak K⁺Currents: Two-Pore Domain Potassium Channels

Molecular Background of Leak K⁺Currents: Two-Pore Domain Potassium Channels