title: Genistein reduces NF-kappa B in T lymphoma cells via a caspase-mediated cleavage of I kappa B alpha.
abstract: The transcription factor NF-kappa B is elevated in murine T-cell lymphoma lines compared with normal thymic lymphocytes, and may play a role in the neoplastic transformation of these cells. When T lymphoma cells were treated with the soy isoflavone genistein, a marked reduction in nuclear NF-kappa B levels was detectable predominantly for the p50/p50 homodimer and p50/p65 heterodimer. To examine the mechanism by which NF-kappa B is reduced by genistein, we analyzed the NF-kappa B inhibitor, I kappa B alpha, and detected a 34 kDa cleavage product Delta I kappa B alpha, which was induced by genistein in a dose-dependent manner. Our observation that a pan-caspase inhibitor could inhibit the induction of Delta I kappa B alpha by genistein suggested that caspase activity was responsible for this cleavage product. In support of this idea, we detected an increase in caspase-3 activity in response to increasing time of genistein exposure. When the induction of Delta I kappa B alpha was prevented, we detected no reduction of NF-kappa B levels by genistein. These results support a direct role for Delta I kappa B alpha in the reduction of NF-kappa B by genistein. To determine the effect of genistein on some NF-kappa B target gene products, we examined the antiapoptotic proteins Bcl-2, Bcl-X(L), A1, and cIAP-1. Only changes in A1 and cIAP-1 levels were affected with significant reductions in response to genistein. Generation of the repressive activity of Delta I kappa B alpha on NF-kappa B is a novel mechanism for the reduction of this transcription factor by genistein and the possible effect this may have on the ability of genistein to induce apoptosis in tumor cells.
authors.affiliation: Department of Immunology and Microbiology, Wayne State University, 540 E. Canfield Ave., Detroit, MI 48201, USA.
authors.forename: Dwayne M
authors.initials: DM
authors.lastname: Baxa
authors.forename: Fayth K
authors.initials: FK
authors.lastname: Yoshimura
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D004789:Enzyme Activation; D019833:Genistein / Q000494:pharmacology*; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism*; D016399:Lymphoma, T-Cell / Q000378:metabolism / Q000473:pathology; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D000072000:NF-KappaB Inhibitor alpha; D019833:Genistein; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases