| Autor: |
Bouchon, B., Papon, J., Communal, Y., Madelmont, J.-C., Degoul, F. |
| Předmět: |
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| Zdroj: |
British Journal of Pharmacology; Oct2007, Vol. 152 Issue 4, p449-455, 7p, 1 Black and White Photograph, 1 Diagram, 1 Chart, 4 Graphs |
| Abstrakt: |
Background and purpose:Phenyl-chloroethyl ureas (CEUs) are a class of anticancer drugs that mainly react with proteins. Two molecules of this family, cyclohexylphenyl-chloroethyl urea (CCEU) and iodophenyl-chloroethyl urea (ICEU) induced G1/S and G2/M cell cycle blocks, respectively. We hypothesised that these observations were linked to a differential protein alkylation pattern.Experimental approach:Proteins from B16 cells incubated with [14C-urea]-CCEU and [125I]-ICEU were compared by 2D-analyses followed by MALDI-TOF identification of modified proteins and characterisation of the CCEU binding. Protein expression was investigated by Western blot analyses and cell cycle data were obtained by flow cytometry.Key results:Several proteins (PDIA1, PDIA3, PDIA6, TRX, VDAC2) were alkylated by both ICEU and CCEU but β-tubulin and prohibitin (PHB) were specifically alkylated by either ICEU or CCEU respectively. Specific alkylation of these two proteins might explain the observed difference in B16 cell cycle arrest in G2 and G1 phases respectively. Mass spectrometry studies on the alkylated prohibitin localised the modified peptide and identified Asp-40 as the target for CCEU. This alkylation induced an increased cellular content of PHB that should contribute to the accumulation of cells in G1 phase.Conclusions and implications:This study reinforces our findings that CEUs alkylate proteins through an ester linkage with an acidic amino acid and shows that PHB alkylation contributes to G1/S arrest in CCEU treated B16 cells. Modification of PHB status and/or activity is an open route for new cancer therapeutics.British Journal of Pharmacology (2007) 152, 449–455; doi:10.1038/sj.bjp.0707415; published online 20 August 2007 [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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