Molecular Pharmacology and Therapeutics, Loyola University, Chicago, IL, USA.
Cell Death Dis. 2013 Jun 6;4(6):e652. doi: 10.1038/cddis.2013.174.
Traditionally the hERG1 potassium channel has been known to have a fundamental role in membrane excitability of several mammalian cells including cardiac myocytes. hERG1 has recently been found to be expressed in non-excitable cancer cells of different histogenesis, but the role of this channel in cancer biology is unknown. Results form recent studies on the effect hERG1 inhibition in some breast cancer cells are controversial as it can lead to apoptosis or protect against cell death. Nevertheless, these data suggest that the hERG1 channel could have an important role in cancer biology. Here we report the effects of hyperstimulation of hERG1 channel in human mammary gland adenocarcinoma-derived cells. Application of the hERG1 activator, the diphenylurea derivative NS1643, inhibits cell proliferation irreversibly. This event is accompanied by a preferential arrest of the cell cycle in G0/G1 phase without the occurrence of apoptotic events. Consequently, cells responded to NS1643 by developing a senescence-like phenotype associated with increased protein levels of the tumor suppressors p21 and p16(INK4a) and by a positive β-galactosidase assay. These data suggest that prolonged stimulation of the hERG1 potassium channel may activate a senescence program and offers a compelling opportunity to develop a potential antiproliferative cancer therapy.
传统上，hERG1 钾通道被认为在包括心肌细胞在内的几种哺乳动物细胞的膜兴奋性中具有基本作用。最近发现 hERG1 在不同组织发生的非兴奋性癌细胞中表达，但该通道在癌症生物学中的作用尚不清楚。最近关于 hERG1 抑制在一些乳腺癌细胞中的作用的研究结果存在争议，因为它可能导致细胞凋亡或防止细胞死亡。然而，这些数据表明 hERG1 通道在癌症生物学中可能具有重要作用。在这里，我们报告了 hERG1 通道超刺激对人乳腺腺癌衍生细胞的影响。hERG1 激活剂二苯脲衍生物 NS1643 的应用不可逆地抑制细胞增殖。这一事件伴随着细胞周期在 G0/G1 期的优先停滞，而没有发生凋亡事件。因此，细胞通过发展与肿瘤抑制因子 p21 和 p16(INK4a)的蛋白水平增加以及阳性β-半乳糖苷酶测定相关的衰老样表型对 NS1643 作出反应。这些数据表明，hERG1 钾通道的长期刺激可能会激活衰老程序，并为开发潜在的抗增殖癌症治疗提供了一个引人注目的机会。
