Oncotarget

Research Papers:

Cisplatin inhibits MEK1/2

Tetsu Yamamoto, Igor F. Tsigelny, Andreas W. Götz and Stephen B. Howell _

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Oncotarget. 2015; 6:23510-23522. https://doi.org/10.18632/oncotarget.4355

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Abstract

Tetsu Yamamoto1, Igor F. Tsigelny1,2,3, Andreas W. Götz3, Stephen B. Howell1

1Moores Cancer Center and Department of Medicine, University of California, San Diego, La Jolla, CA 92093

2Neuroscience Department, University of California, San Diego, La Jolla, CA 92093

3San Diego Supercomputer Center, University of California, San Diego, La Jolla, CA 92093

Correspondence to:

Stephen B. Howell, e-mail: [email protected]

Keywords: MEK1, RAS, ERK, copper, cisplatin

Received: March 11, 2015     Accepted: June 09, 2015     Published: June 20, 2015

ABSTRACT

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 μM and MEK1/2 in whole cells with an IC50 of 37.4 μM. 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.


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