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首页> 美国政府科技报告 >Chemoprevention by Elimination of Cancer-Prone, Mutant p53-Containing Breast Cells
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Chemoprevention by Elimination of Cancer-Prone, Mutant p53-Containing Breast Cells

机译：通过消除癌症易感，突变的含p53乳腺细胞进行化学预防

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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 is because reduced protein synthesis. 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.

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