Genistein reduces NF-kappa B in T lymphoma cells via a caspase-mediated cleavage of I kappa B alpha.
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.
Baxa
Dwayne M
DM
Department of Immunology and Microbiology, Wayne State University, 540 E. Canfield Ave., Detroit, MI 48201, USA.
Yoshimura
Fayth K
FK
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
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