Mechanisms of organoselenium compounds in chemoprevention: effects on transcription factor-DNA binding.
Data obtained on the effects of selenium compounds on regulatory transcription factor-DNA binding by other laboratories are briefly reviewed, and some of our own results in this area are also presented. We assessed the in vitro and in vivo effects of the organoselenium compound 1,4-phenylenebis(methylene)selenocyanate (p-XSC) on the binding activities of the transcription factors nuclear factor-kappa B (NF-kappa B), activator protein-1 (AP-1), Sp1, and Sp3 using the HCT-116 (human colorectal adenocarcinoma) cell line as a model system. Using nuclear extracts, electrophoretic mobility shift assays were carried out to determine the extent of binding of the transcription factors to their respective consensus recognition sites on radiolabeled oligonucleotides. p-XSC and sodium selenite reduced the consensus site binding activity of NF-kappa B in a concentration-dependent manner when nuclear extracts from cells stimulated with tumor necrosis factor-alpha were incubated with either compound ("in vitro"). However, only p-XSC inhibited NF-kappa B consensus recognition site binding when the cells were pretreated with either compound and were then stimulated with tumor necrosis factor-alpha ("in vivo"). In contrast, the consensus site binding activity of AP-1 was inhibited only with sodium selenite, but not with p-XSC in vitro or in vivo. p-XSC or sodium selenite reduced the consensus site binding of transcription factors Sp1 and Sp3 in concentration- and time-dependent manners when nuclear extracts from cells treated with either compound in vivo were assayed by electrophoretic mobility shift assay. 1,4-Phenylenebis(methylene)thiocyanate, the sulfur analog of p-XSC, which is inactive in chemoprevention, had no effect on the oligonucleotide binding of Sp1 and Sp3. Our observations could provide further clues as to the mechanisms involved in the chemoprevention of cancer by p-XSC.
Youn
B W
BW
American Health Foundation, Valhalla, NY 10595, USA.
Fiala
E S
ES
Sohn
O S
OS
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D016384:Consensus Sequence / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D016566:Organoselenium Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D014157:Transcription Factors / Q000187:drug effects / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D016588:Anticarcinogenic Agents; D004268:DNA-Binding Proteins; D016328:NF-kappa B; D016566:Organoselenium Compounds; D014157:Transcription Factors; C074153:1,4-phenylenebis(methylene)selenocyanate