title: Bortezomib induces nuclear translocation of IκBα resulting in gene-specific suppression of NF-κB--dependent transcription and induction of apoptosis in CTCL.
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.
authors.affiliation: Department of Biological Sciences, St. John's University, 8000 Utopia Parkway, Queens, NY 11439, USA.
authors.forename: Ashish
authors.initials: A
authors.lastname: Juvekar
authors.forename: Subrata
authors.initials: S
authors.lastname: Manna
authors.forename: Sitharam
authors.initials: S
authors.lastname: Ramaswami
authors.forename: Tzu-Pei
authors.initials: TP
authors.lastname: Chang
authors.forename: Hai-Yen
authors.initials: HY
authors.lastname: Vu
authors.forename: Chandra C
authors.initials: CC
authors.lastname: Ghosh
authors.forename: Mahmut Y
authors.initials: MY
authors.lastname: Celiker
authors.forename: Ivana
authors.initials: I
authors.lastname: Vancurova
mesh_terms: D017209:Apoptosis / Q000235:genetics*; D001483:Base Sequence; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D004273:DNA, Neoplasm / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D052138:Genes, Neoplasm / Q000235:genetics; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism*; D007976:Leupeptins / Q000494:pharmacology; D016410:Lymphoma, T-Cell, Cutaneous / Q000235:genetics* / Q000473:pathology; D008969:Molecular Sequence Data; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D021122:Protein Subunits / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D011719:Pyrazines / Q000494:pharmacology*; D051996:Transcription Factor RelA / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: D001897:Boronic Acids; D004273:DNA, Neoplasm; D020672:I-kappa B Proteins; D007976:Leupeptins; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; C000606204:NFKBIA protein, human; D021122:Protein Subunits; D011719:Pyrazines; D051996:Transcription Factor RelA; D000072000:NF-KappaB Inhibitor alpha; D000069286:Bortezomib; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde