Liu Lijun, Askari Amir
Department of Physiology, Pharmacology, Metabolism, and Cardiovascular Sciences Medical University of Ohio, Toledo, Ohio 43614-5804, USA.
Cell Mol Biol (Noisy-le-grand). 2006 Dec 30;52(8):28-30.
Therapeutic concentrations of digitalis drugs inhibit the proliferation of breast cancer cells by inducing the interaction of Na+/K+-ATPase with Src/EGFR, activation of ERK1/2, and the resulting upregulation of cell cycle inhibitor p21Cip1. Quantitative comparison of ouabain dose-response curves for growth arrest and pump inhibition shows that ratio of Ki (pump)/Ki (proliferation) = 7.2. Such large gains in sensitivity are characteristic of several signal transducing pathways of other receptors. Making the reasonable assumption that Na+/K+-ATPase is the only receptor for ouabain, the large amplification factor clearly shows that occupation of a small fraction of pumping Na+/K+-ATPase by digitalis drugs, or endogenous digitalis-like factors, is sufficient to cause near complete inhibition of cell growth. The likely causes of large amplification factor in the signaling function of Na+/K+-ATPase include (a) interactions among the protomers of Na+/K+-ATPase in the membrane; and (b) induced clustering of Na+/K+-ATPase oligomers with neighboring proteins. The upstream location of both mechanisms suggests that similar amplifications also occur in other cell types with different digitalis downstream effects; e.g., stimulation of proliferation or hypertrophy.
洋地黄类药物的治疗浓度通过诱导钠钾ATP酶与Src/表皮生长因子受体（EGFR）相互作用、激活细胞外调节蛋白激酶1/2（ERK1/2）以及上调细胞周期抑制剂p21Cip1来抑制乳腺癌细胞的增殖。哇巴因对生长抑制和泵抑制的剂量反应曲线的定量比较显示，抑制常数Ki（泵）/Ki（增殖）=7.2。如此高的敏感性增益是其他受体的几种信号转导途径的特征。做出合理假设，即钠钾ATP酶是哇巴因的唯一受体，这种大的放大因子清楚地表明，洋地黄类药物或内源性类洋地黄因子占据一小部分钠钾ATP酶泵，就足以导致细胞生长几乎完全被抑制。钠钾ATP酶信号功能中出现大放大因子的可能原因包括：（a）膜中钠钾ATP酶亚基之间的相互作用；（b）钠钾ATP酶寡聚体与相邻蛋白质的诱导聚集。这两种机制的上游位置表明，在具有不同洋地黄下游效应的其他细胞类型中也会发生类似的放大；例如，刺激增殖或肥大。
