Digitalis-induced signaling by Na+/K+-ATPase in human breast cancer cells
Digitalis-induced signaling by Na+/K+-ATPase in human breast cancer cells
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DOI：
10.1124/mol.104.007302
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发表时间：
2005-03-01
影响因子：
3.6
通讯作者：
Askari, A
中科院分区：
文献类型：
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作者：
Kometiani, P;Liu, LJ;Askari, A
由于流行病学研究表明洋地黄对乳腺癌患者有良好的治疗效果，我们探讨了这些药物对雌激素受体阴性的人乳腺癌细胞株MDA-MB-435s的生长抑制作用的机制。哇巴因浓度(100 nM或更低)对Na+/K+-ATPase泵功能的抑制小于25%，对细胞活力无影响，但对细胞增殖有抑制作用。在相同浓度下，哇巴因1)激活了Src激酶，并刺激了Src和Na+/K+-ATPase与表皮生长因子受体(EGFR)的相互作用；2)引起了细胞外信号调节蛋白1和2(ERK1/2)的短暂并持续激活；3)增加了p21(Cip1)的表达，但下调了P53的表达；4)激活了c-jun NH2末端激酶(JNK)，但不激活了p38激酶。这些数据结合我们之前关于Na+/K+-ATPase在其他细胞中的信号作用的发现，表明哇巴因通过Na+/K+-ATPase激活/反式激活Src/EGFR导致ERK1/2激活，从而导致细胞周期抑制物p21Cip1水平的增加，并导致生长停滞。还建议JNK与ERK1/2在这一进程中进行合作。地高辛和洋地黄的浓度接近或达到治疗血浆水平，对细胞增殖和ERK1/2的影响与哇巴因相似，支持洋地黄药物治疗乳腺癌的潜在价值。
Because beneficial effects of digitalis treatment in breast cancer patients have been suggested by epidemiological studies, we explored the mechanism of the growth inhibitory effects of these drugs on the estrogen receptor-negative human breast cancer cell line MDA-MB-435s. Ouabain concentrations (100 nM or lower) that caused less than 25% inhibition of the pumping function of Na+/K+-ATPase had no effect on cell viability but inhibited proliferation. At the same concentrations, ouabain 1) activated Src kinase and stimulated the interaction of Src and Na+/K+-ATPase with epidermal growth factor receptor ( EGFR); 2) caused a transient and then a sustained activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2); 3) increased the expression of p21(Cip1) but decreased that of p53; and 4) activated c-Jun NH2-terminal kinase (JNK) but not p38 kinase. These data, in conjunction with our previous findings on the signaling role of Na+/K+-ATPase in other cells, suggest that ouabain-induced activation/transactivation of Src/EGFR by Na+/K+-ATPase leads to activation of ERK1/2, the resulting increase in the level of cell cycle inhibitor p21Cip1, and growth arrest. Cooperation of JNK with ERK1/2 in this process is also suggested. Digoxin and digitoxin concentrations close to or at the therapeutic plasma levels had effects on proliferation and ERK1/2 similar to those of ouabain, supporting the proposed potential value of digitalis drugs for the treatment of breast cancer.