1. Bortezomib induces nuclear translocation of IκBα resulting in gene-specific suppression of NF-κB--dependent transcription and induction of apoptosis in CTCL.
- Author
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Juvekar A, Manna S, Ramaswami S, Chang TP, Vu HY, Ghosh CC, Celiker MY, and Vancurova I
- Subjects
- Base Sequence, Bortezomib, Cell Line, Tumor, Cell Nucleus drug effects, DNA, Neoplasm metabolism, Drug Screening Assays, Antitumor, Gene Expression Regulation, Neoplastic drug effects, Genes, Neoplasm genetics, Humans, Leupeptins pharmacology, Lymphoma, T-Cell, Cutaneous pathology, Molecular Sequence Data, NF-KappaB Inhibitor alpha, NF-kappa B genetics, NF-kappa B p50 Subunit metabolism, Protein Binding drug effects, Protein Subunits metabolism, Protein Transport drug effects, Transcription Factor RelA metabolism, Apoptosis genetics, Boronic Acids pharmacology, Cell Nucleus metabolism, I-kappa B Proteins metabolism, Lymphoma, T-Cell, Cutaneous genetics, NF-kappa B metabolism, Pyrazines pharmacology, Transcription, Genetic drug effects
- Abstract
Cutaneous T-cell lymphoma (CTCL) is characterized by constitutive activation of nuclear factor κB (NF-κB), which plays a crucial role in the survival of CTCL cells and their resistance to apoptosis. NF-κB 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-κB activity in CTCL Hut-78 cells. We demonstrate that bortezomib and MG132 suppress NF-κB activity in Hut-78 cells by a novel mechanism that consists of inducing nuclear translocation and accumulation of IκBα (nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha), which then associates with NF-κB p65 and p50 in the nucleus and inhibits NF-κB DNA binding activity. Surprisingly, however, while expression of NF-κB-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-κB 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-κB-dependent gene expression by bortezomib is gene specific and depends on the subunit composition of NF-κB dimers recruited to NF-κB-responsive promoters.
- Published
- 2011
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