Calcium-activated potassium channels BK and IK1 are functionally expressed in human gliomas but do not regulate cell proliferation.
Calcium-activated potassium channels BK and IK1 are functionally expressed in human gliomas but do not regulate cell proliferation.
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DOI：
10.1371/journal.pone.0012304
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发表时间：
2010-08-20
期刊：
影响因子：
3.7
通讯作者：
Kuo YH
中科院分区：
文献类型：
--
作者：
Abdullaev IF;Rudkouskaya A;Mongin AA;Kuo YH
胶质瘤是一种病态脑瘤，对现有的化疗和放射治疗具有极强的抵抗力。一些研究表明，钙激活的钾通道有助于肿瘤细胞的高增殖潜力，包括胶质瘤。然而，其他文献没有显示这些通道的作用，甚至指定它们具有抗肿瘤作用。在这项工作中，我们研究了人胶质母细胞瘤细胞中钙激活的K+通道的表达及其对细胞增殖的功能贡献。定量RT-PCR检测了两个胶质母细胞瘤来源细胞系和一个多形性胶质母细胞瘤手术标本中大电导(BK)、中电导(IK1)和小电导(SK2)K+通道的转录。通过全细胞电生理记录证实BK和IK1在U251和U87胶质瘤细胞系和原代培养的胶质瘤细胞中的功能表达。BK(paxilline和penitrem A)和IK1通道(克霉唑和TRAM-34)的抑制剂以相加的方式抑制U251和U87的增殖，而SK通道的选择性阻断剂UCL1848则无作用。然而，BK和IK1抑制剂的抗增殖特性在高于抑制通道活性所需的浓度时被看到。为了验证药物的特异性，我们使用基因特异性siRNAs下调了U251细胞中的BK和IK1通道。虽然siRNA敲除导致BK和IK1电流密度显著降低，但单基因沉默和双基因沉默都不会显著影响增殖率。综上所述，这些结果表明，钙激活的K+通道在胶质瘤细胞的增殖中并不起关键作用，药物抑制剂的作用是通过其非靶点作用实现的。
Gliomas are morbid brain tumors that are extremely resistant to available chemotherapy and radiology treatments. Some studies have suggested that calcium-activated potassium channels contribute to the high proliferative potential of tumor cells, including gliomas. However, other publications demonstrated no role for these channels or even assigned them antitumorogenic properties. In this work we characterized the expression and functional contribution to proliferation of Ca2+-activated K+ channels in human glioblastoma cells. Quantitative RT-PCR detected transcripts for the big conductance (BK), intermediate conductance (IK1), and small conductance (SK2) K+ channels in two glioblastoma-derived cell lines and a surgical sample of glioblastoma multiforme. Functional expression of BK and IK1 in U251 and U87 glioma cell lines and primary glioma cultures was verified using whole-cell electrophysiological recordings. Inhibitors of BK (paxilline and penitrem A) and IK1 channels (clotrimazole and TRAM-34) reduced U251 and U87 proliferation in an additive fashion, while the selective blocker of SK channels UCL1848 had no effect. However, the antiproliferative properties of BK and IK1 inhibitors were seen at concentrations that were higher than those necessary to inhibit channel activity. To verify specificity of pharmacological agents, we downregulated BK and IK1 channels in U251 cells using gene-specific siRNAs. Although siRNA knockdowns caused strong reductions in the BK and IK1 current densities, neither single nor double gene silencing significantly affected rates of proliferation. Taken together, these results suggest that Ca2+-activated K+ channels do not play a critical role in proliferation of glioma cells and that the effects of pharmacological inhibitors occur through their off-target actions.
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影响因子：
4.1
作者：
Khalid, MH;Shibata, S;Hiura, T
通讯作者：
Hiura, T
影响因子：
1.7
作者：
Basrai, D;Kraft, R;Patt, S
通讯作者：
Patt, S
影响因子：
8
作者：
Bloch, M.;Ousingsawat, J.;Bubendorf, L.
通讯作者：
Bubendorf, L.
DOI：
10.4161/cc.8.21.9888
发表时间：
2009-11-01
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
--
作者：
Blackiston DJ;McLaughlin KA;Levin M
通讯作者：
Levin M
影响因子：
2.9
作者：
BRISMAR, T;COLLINS, VP
通讯作者：
COLLINS, VP