Department of Biology, University of Padova, Italy.
Curr Pharm Des. 2014;20(2):189-200. doi: 10.2174/13816128113199990032.
Plasma membrane (PM) and mitochondrial (mt) ion channels - particularly potassium channels - became oncological targets soon after the discovery that they are involved both in the regulation of proliferation and apoptosis. Some members of the Kv Shaker family, namely Kv1.1, Kv1.3, Kv1.5 and Kv11.1 (Herg), and the intermediate-conductance calcium-activated potassium KCa3.1 (IK) channels have been shown to contribute to apoptosis in various cell lines. Kv1.3, Kv1.5 and IK are located in the plasma membrane but also in the mitochondrial inner membrane, where they participate in apoptotic signalling. Interestingly, an altered protein expression of some of the channels mentioned above has been reported in neoplastic cell lines/tissues, but a systematic quantification addressing the protein expression of the above potassium channels in tumor cell lines of different origin has not been carried out yet. In the present study we investigated whether expression of specific potassium channels, at the mRNA and protein level, can be correlated with cell sensitivity to various apoptotic stimuli, including chemotherapeutic drugs, in a panel of cancer cell lines. The results show correlation between the protein expression of the Kv1.1 and Kv1.3 channels and susceptibility to death upon treatment with staurosporine, C2-ceramide and cisplatin. Furthermore, we investigated the correlation between Kv channel expression and sensitivity to three distinct membrane-permeant Kv1.3 inhibitors, since these drugs have recently been shown to be able to induce apoptosis and also reduce tumor volume in an in vivo model. Higher protein expression of Kv1.3 significantly correlated with lower cell survival upon treatment with clofazimine, one of the Kv1.3 inhibitors. These results suggest that expression of Kv1.1 and Kv1.3 sensitizes tumour cells of various origins to cytotoxins. Data reported in this work regarding potassium channel protein expression in different cancer cell lines may be exploited for pharmacological manipulation aiming to affect proliferation/apoptosis of cancer cells.
质膜（PM）和线粒体（mt）离子通道 - 特别是钾通道 - 在发现它们参与增殖和凋亡的调节后不久就成为了肿瘤学的靶点。Kv Shaker 家族的一些成员，即 Kv1.1、Kv1.3、Kv1.5 和 Kv11.1（Herg）以及中电导钙激活钾 KCa3.1（IK）通道，已被证明在各种细胞系中有助于细胞凋亡。Kv1.3、Kv1.5 和 IK 位于质膜中，但也位于线粒体内膜中，在那里它们参与凋亡信号转导。有趣的是，已经报道了上述一些通道的蛋白质表达在肿瘤细胞系/组织中发生改变，但尚未对不同来源的肿瘤细胞系中上述钾通道的蛋白质表达进行系统定量。在本研究中，我们研究了在一组癌症细胞系中，特定钾通道的 mRNA 和蛋白质水平的表达是否可以与对各种凋亡刺激的细胞敏感性相关，包括化疗药物。结果表明，Kv1.1 和 Kv1.3 通道的蛋白质表达与用 staurosporine、C2-神经酰胺和顺铂处理后的细胞死亡敏感性相关。此外，我们研究了 Kv 通道表达与三种不同的膜通透 Kv1.3 抑制剂敏感性之间的相关性，因为这些药物最近已被证明能够诱导凋亡并在体内模型中减少肿瘤体积。Kv1.3 的蛋白质表达较高与用氯法齐明（Kv1.3 抑制剂之一）处理后的细胞存活率降低显著相关。这些结果表明，Kv1.1 和 Kv1.3 的表达使各种来源的肿瘤细胞对细胞毒素敏感。本工作中关于不同癌症细胞系中钾通道蛋白质表达的数据可用于药理学操作，旨在影响癌细胞的增殖/凋亡。
