Most known chemopreventive agents including certain selenium compounds suppress the activation of the nuclear factor κB (NF-κB), but the mechanisms remain largely elusive. Toward this end, we initially showed that the inhibition of NF-κB DNA binding by benzyl selenocyanate (BSC) and 1,4-phenylenebis(methylene)selenocyanate (p-XSC) was reversed by the addition of DTT; this suggests the formation of DTT-reducible selenium-sulfur bonds between selenocyanate moieties and cysteine residues in NF-κB (p50) protein. Furthermore, the inhibitory effect of selenocyanates on NF-κB was not altered in the presence of physiologic level of reduced glutathione (1 mmol/L), suggesting that selenocyanates can also inhibit NF-κB in vivo. Using both matrix-assisted laser desorption/ionization-time of flight and tandem mass spectrometry fragmentation, we showed for the first time that the Cys 62 residue in the active site of NF-κB (p50) protein was modified by BSC through the formation of a selenium-sulfur bond. In addition, p-XSC-bound NF-κB (p50) protein was also detected by a radiotracer method. To provide further support, molecular models of both BSC and p-XSC positioned in the DNA binding pocket of the p50 were constructed through the covalent modification of Cys62; the models reveal that DNA substrate could be hindered to enter its DNA binding region. This study shows for the first time that BSC and p-XSC may exert their chemopreventive activity, at least in part, by inhibiting NF-κB through covalent modification of Cys62 of the p50 subunit of NF-κB.
All Science Journal Classification (ASJC) codes
- Cancer Research