Cisplatin inhibits MEK1/2

被引:8
|
作者
Yamamoto, Tetsu [1 ,2 ]
Tsigelny, Igor F. [1 ,2 ,3 ,4 ]
Goetz, Andreas W. [4 ]
Howell, Stephen B. [1 ,2 ]
机构
[1] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA
[2] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA
[3] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA
[4] Univ Calif San Diego, San Diego Supercomp Ctr, La Jolla, CA 92093 USA
基金
美国国家卫生研究院;
关键词
MEK1; RAS; ERK; copper; cisplatin; COPPER CHAPERONE ATOX1; METAL-BINDING; SUPEROXIDE-DISMUTASE; FLUORESCENT SENSOR; CELLS; PROTEIN; PROMOTES; DOMAINS; ATP7B;
D O I
10.18632/oncotarget.4355
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Cisplatin (cDDP) is known to bind to the CXXC motif of proteins containing a ferrodoxin-like fold but little is known about its ability to interact with other Cu-binding proteins. MEK1/2 has recently been identified as a Cu-dependent enzyme that does not contain a CXXC motif. We found that cDDP bound to and inhibited the activity of recombinant MEK1 with an IC50 of 0.28 mu M and MEK1/2 in whole cells with an IC50 of 37.4 mu M. The inhibition of MEK1/2 was relieved by both Cu+1 and Cu+2 in a concentration-dependent manner. cDDP did not inhibit the upstream pathways responsible for activating MEK1/2, and did not cause an acute depletion of cellular Cu that could account for the reduction in MEK1/2 activity. cDDP was found to bind MEK1/2 in whole cells and the extent of binding was augmented by supplementary Cu and reduced by Cu chelation. Molecular modeling predicts 3 Cu and cDDP binding sites and quantum chemistry calculations indicate that cDDP would be expected to displace Cu from each of these sites. We conclude that, at clinically relevant concentrations, cDDP binds to and inhibits MEK1/2 and that both the binding and inhibitory activity are related to its interaction with Cu bound to MEK1/2. This may provide the basis for useful interactions of cDDP with other drugs that inhibit MAPK pathway signaling.
引用
收藏
页码:23510 / 23522
页数:13
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