Abstract

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.

Original languageEnglish (US)
Pages (from-to)10475-10483
Number of pages9
JournalCancer Research
Volume67
Issue number21
DOIs
StatePublished - Nov 1 2007

Fingerprint

DNA
Selenium
Sulfur
Selenium Compounds
Proteins
Molecular Models
Tandem Mass Spectrometry
Glutathione
Cysteine
Catalytic Domain
Lasers
benzyl selenocyanate
selenocyanic acid
1,4-phenylenebis(methylene)selenocyanate

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

@article{d8159fcdfc4c4108af5bc29f65eadfdd,
title = "Inhibition of nuclear factor-κB DNA binding by organoselenocyanates through covalent modification of the p50 subunit",
abstract = "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.",
author = "Chen, {Kun Ming} and Spratt, {Thomas E.} and Stanley, {Bruce A.} and {De Cotiis}, {Dan A.} and Bewley, {Maria C.} and Flanagan, {John M.} and Dhimant Desai and Arunangshu Das and Fiala, {Emerich S.} and Shantu Amin and Karam El-Bayoumy",
year = "2007",
month = "11",
day = "1",
doi = "10.1158/0008-5472.CAN-07-2510",
language = "English (US)",
volume = "67",
pages = "10475--10483",
journal = "Cancer Research",
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TY - JOUR

T1 - Inhibition of nuclear factor-κB DNA binding by organoselenocyanates through covalent modification of the p50 subunit

AU - Chen, Kun Ming

AU - Spratt, Thomas E.

AU - Stanley, Bruce A.

AU - De Cotiis, Dan A.

AU - Bewley, Maria C.

AU - Flanagan, John M.

AU - Desai, Dhimant

AU - Das, Arunangshu

AU - Fiala, Emerich S.

AU - Amin, Shantu

AU - El-Bayoumy, Karam

PY - 2007/11/1

Y1 - 2007/11/1

N2 - 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.

AB - 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.

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U2 - 10.1158/0008-5472.CAN-07-2510

DO - 10.1158/0008-5472.CAN-07-2510

M3 - Article

C2 - 17974991

AN - SCOPUS:35948989659

VL - 67

SP - 10475

EP - 10483

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 21

ER -