title: Cisplatin inhibits MEK1/2.
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.
authors.affiliation: Moores Cancer Center and Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Tetsu
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: Moores Cancer Center and Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.|Neuroscience Department, University of California, San Diego, La Jolla, CA 92093, USA.|San Diego Supercomputer Center, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Igor F
authors.initials: IF
authors.lastname: Tsigelny
authors.affiliation: San Diego Supercomputer Center, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Andreas W
authors.initials: AW
authors.lastname: Götz
authors.affiliation: Moores Cancer Center and Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Howell
mesh_terms: D020816:Amino Acid Motifs; D000970:Antineoplastic Agents / Q000494:pharmacology; D001665:Binding Sites; D045744:Cell Line, Tumor; D002474:Cell-Free System; D002614:Chelating Agents / Q000737:chemistry; D002945:Cisplatin / Q000737:chemistry*; D003300:Copper / Q000737:chemistry; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D048369:MAP Kinase Kinase 1 / Q000378:metabolism*; D048370:MAP Kinase Kinase 2 / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008958:Models, Molecular; D010766:Phosphorylation; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D013050:Spectrometry, Fluorescence
chemical_list: D000970:Antineoplastic Agents; D002614:Chelating Agents; D011994:Recombinant Proteins; D003300:Copper; C482128:MAP2K2 protein, human; D048049:Extracellular Signal-Regulated MAP Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human; D002945:Cisplatin
keywords: ERK; MEK1; RAS; cisplatin; copper