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.

Key Players of Cisplatin Resistance: Towards a Systems Pharmacology Approach

“…The number of differentially expressed genes annotated with these twelve terms was far too large for further analysis. Therefore, we focused on those terms, for which a contribution to the mode of action of cisplatin or possible involvement in chemoresistance has been described in the literature, namely NOTCH receptor signalling [ 24 , 25 ], the VEGFR signalling pathway [ 26 , 27 ], the cell surface receptor signalling pathway [ 28 , 29 ] and the Ras protein signal transduction pathway [ 30 , 31 ].…”

“…DOK1 is known as a negative regulator of Ras [ 36 , 39 ]. HRas belongs to the Ras oncogene family being central to the MAPK/ERK pathway [ 30 ]. However, the analysis of ERK activation revealed no significant differences between sensitive and resistant cell line ( Figure 5 ).…”

MAST1 Drives Cisplatin Resistance in Human Cancers by Rewiring cRaf-Independent MEK Activation

“…The specific structure of cisplatin may disrupt the MEK1-cRaf complex resulting in MAST1 as the sole kinase remaining in the complex. Previous reports showed that cRaf binding sites in MEK1 consist of Ser221/217, whereas predicted cisplatin binding sites in MEK1 are Met56 and Cys104 (Caunt et al, 2015; Yamamoto et al, 2015). We revealed that cisplatin directly binds to MEK1 but not cRaf.…”

Pulling a MAST1 on Cisplatin Resistance

“…Over a time course of cisplatin treatment in resistant and sensitive cell lines, the authors show that cRAF is displaced from MEK1 within as little as 1 hr of cisplatin exposure. Cysteine 142 was previously predicted as one of the copper-binding sites in MEK1 (Yamamoto et al, 2015), so it is tempting to speculate that cisplatin may displace copper from MEK1. It would also be intriguing to determine whether cisplatin resistance markers, notably the copper efflux transporters (ATP7A, ATP7B), are upregulated during cisplatin treatment to decrease competition by copper for binding to MEK1 (Turski et al, 2012).…”