Genistein reduces NF-κB in T lymphoma cells via a caspase-mediated cleavage of IκBα

The transcription factor NF-kappaB 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-kappaB levels was detectable predominantly for the p50/p50 homodimer and p50/p65 heterodimer. To examine the mechanism by which NF-kappaB is reduced by genistein, we analyzed the NF-kappaB inhibitor, IkappaBalpha, and detected a 34 kDa cleavage product DeltaIkappaBalpha, which was induced by genistein in a dose-dependent manner. Our observation that a pan-caspase inhibitor could inhibit the induction of DeltaIkappaBalpha 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 DeltaIkappaBalpha was prevented, we detected no reduction of NF-kappaB levels by genistein. These results support a direct role for DeltaIkappaBalpha. in the reduction of NF-kappaB by genistein. To determine the effect of genistein on some NF-kappaB 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 DeltaIkappaBalpha on NF-kappaB 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. (C) 2003 Elsevier Inc. All rights reserved.