Cardiac glycosides inhibit p53 synthesis by a mechanism relieved by Src or MAPK inhibition.
Cardiac glycosides inhibit p53 synthesis by a mechanism relieved by Src or MAPK inhibition.
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DOI：
10.1158/0008-5472.can-09-0891
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发表时间：
2009-08-15
期刊：
影响因子：
11.2
通讯作者：
Sun Y
中科院分区：
文献类型：
--
作者：
Wang Z;Zheng M;Li Z;Li R;Jia L;Xiong X;Southall N;Wang S;Xia M;Austin CP;Zheng W;Xie Z;Sun Y
P53在多个水平上受到调控。我们在这里报道了多个人类癌细胞系中的P53被心脏苷类药物地高辛或哇巴因下调，地高辛或哇巴因是Na+/K+-ATPase的有效抑制剂。这些药物以剂量、时间和癌细胞系依赖的方式在纳摩尔浓度下降低P53蛋白的基础水平，但与野生型(Wt)或突变体的P53状态无关。这些药物还降低了其激活剂诱导的P53水平，以及转染到人类癌细胞中的P53水平，无论其状态如何。有趣的是，这些药物对两个永生化的人类细胞系中的内源性P53没有影响。从机制上讲，P53的减少不是发生在mRNA水平，而是发生在蛋白质水平，这是蛋白质合成减少而不是加速降解的结果。不同细胞系对药物诱导的P53降低的敏感性与Na+/K+-α酶亚基的水平无关。虽然降低细胞外K+并不像哇巴因和地高辛那样降低P53，但它确实增强了地高辛和哇巴因在敏感系中诱导的P53降低。最后，当药物与Na+/K+-ATPase结合时，可能通过激活Src/MAPK信号通路来触发P53的降低，并可被Src或MEK的抑制剂完全阻断。这是首次报道心脏苷类药物通过启动Src/MAPK信号通路，通过抑制P53蛋白的合成来降低P53的水平。这些药物可能对治疗具有功能获得型p53突变的人类癌症有用。
p53 is regulated at the multiple levels. We report here that p53 in multiple lines of human cancer cells is down-regulated by cardiac glycoside drugs, digoxin or ouabain, the potent inhibitors of Na+/K+-ATPase. These drugs reduced the basal levels of p53 protein at nanomolar concentrations in a dose-, time- and cancer cell line-dependent manner, but independent of p53 status of wild type (wt) or mutant. The drugs also reduced the levels of p53 induced by its activators as well as p53 transfected into human cancer cells, regardless of its status. Interestingly, the drugs had no effect on endogenous p53 in two immortalized human cell lines. Mechanistically, p53 reduction did not occur at the mRNA levels, but at the protein levels, as a result of reduced protein synthesis rather than enhanced degradation. The cellular sensitivity to drug-induced p53 reduction was not associated with the levels of α subunits of Na+/K+-ATPase in different cell lines. While lowering extracellular K+ did not reduce p53 as did ouabain and digoxin, it did potentiate both digoxin and ouabain-induced p53 reduction in sensitive lines. Finally, p53 reduction appears to be triggered by activation of Src/MAPK signaling pathways upon drug binding to the Na+/K+-ATPase and can be completely blocked by the inhibitors of Src or MEK. This is the first report that cardiac glycoside drugs, by initiating the Src/MAPK signaling pathways, reduce the p53 levels via inhibition of p53 protein synthesis. The drugs may be useful in the treatment of human cancers with a gain-of-function p53 mutation.