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Inhibition of Nuclear Factor-B DNA Binding by Organoselenocyanates through Covalent Modification of the p50 Subunit

¹ Department of Biochemistry and Molecular Biology, ² Proteomics/Mass Spectrometry Core Facility of the Section of Research Resources, and ³ Department of Pharmacology, Penn State College of Medicine, Hershey, Pennsylvania and ⁴ New York University School of Medicine, Tuxedo, New York

Requests for reprints: Karam El-Bayoumy, Department of Biochemistry and Molecular Biology, Penn State College of Medicine, H171, 500 University Drive, Hershey, PA 17033. Phone: 717-531-1005; Fax: 717-531-0002; E-mail: kee2{at}psu.edu.

Most known chemopreventive agents including certain selenium compounds suppress the activation of the nuclear factor B (NF-B), but the mechanisms remain largely elusive. Toward this end, we initially showed that the inhibition of NF-B 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-B (p50) protein. Furthermore, the inhibitory effect of selenocyanates on NF-B was not altered in the presence of physiologic level of reduced glutathione (1 mmol/L), suggesting that selenocyanates can also inhibit NF-B 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 Cys⁶² residue in the active site of NF-B (p50) protein was modified by BSC through the formation of a selenium-sulfur bond. In addition, p-XSC–bound NF-B (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-B through covalent modification of Cys⁶² of the p50 subunit of NF-B. [Cancer Res 2007;67(21):10475–83]

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