Bortezomib Induces Nuclear Translocation of IκBα Resulting in Gene-Specific Suppression of NF-κB-Dependent Transcription and Induction of Apoptosis in CTCL

Cutaneous T-cell lymphoma (CTCL) is characterized by constitutive activation of nuclear factor kappa B (NF-kappa B), which plays a crucial role in the survival of CTCL cells and their resistance to apoptosis. NF-kappa B activity in CTCL is inhibited by the proteasome inhibitor bortezomib; however, the mechanisms remained unknown. In this study, we investigated mechanisms by which bortezomib suppresses NF-kappa B activity in CTCL Hut-78 cells. We demonstrate that bortezomib and MG132 suppress NF-kappa B activity in Hut-78 cells by a novel mechanism that consists of inducing nuclear translocation and accumulation of I kappa B alpha (nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha), which then associates with NF-kappa B p65 and p50 in the nucleus and inhibits NF-kappa B DNA binding activity. Surprisingly, however, while expression of NF-kappa B-dependent antiapoptotic genes cIAP1 and cIAP2 is inhibited by bortezomib, expression of Bcl-2 is not suppressed. Chromatin immunoprecipitation indicated that cIAP1 and cIAP2 promoters are occupied by NF-kappa B p65/50 heterodimers, whereas Bcl-2 promoter is occupied predominantly by p50/50 homodimers. Collectively, our data reveal a novel mechanism of bortezomib function in CTCL and suggest that the inhibition of NF-kappa B-dependent gene expression by bortezomib is gene specific and depends on the subunit composition of NF-kappa B dimers recruited to NF-kappa B-responsive promoters. Mol Cancer Res; 9(2); 183-94. (C) 2011 AACR.