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 kB (NF-kB), which plays a crucial role in the survival of CTCL cells and their resistance to apoptosis. NF-kB 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-kB activity in CTCL Hut-78 cells. We demonstrate that bortezomib and MG132 suppress NF-kB activity in Hut-78 cells by a novel mechanism that consists of inducing nuclear translocation and accumulation of IkBa (nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha), which then associates with NF-kB p65 and p50 in the nucleus and inhibits NF-kB DNA binding activity. Surprisingly, however, while expression of NF-kB-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-kB 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-kB-dependent gene expression by bortezomib is gene specific and depends on the subunit composition of NF-kB dimers recruited to NF-kB-responsive promoters. Mol Cancer Res; 9(2); 183-94. Ó2011 AACR.

Proteasome Inhibition Increases Recruitment of IκB Kinase β (IKKβ), S536P-p65, and Transcription Factor EGR1 to Interleukin-8 (IL-8) Promoter, Resulting in Increased IL-8 Production in Ovarian Cancer Cells

“…1B) cells. This was consistent with our previous studies demonstrating that in prostate cancer and leukemia cells, proteasome inhibition induces translocation of IB␣ from the cytoplasm to the nucleus, resulting in a gene-specific repression of NFB-dependent transcription (33)(34)(35). In contrast to p65 or IB␣, BZ did not have any pronounced effect on the nuclear levels of p50 in OVCAR3 and SKOV3 cells (Fig.…”

HHV-8-negative, idiopathic multicentric Castleman disease: novel insights into biology, pathogenesis, and therapy

“…[94][95][96] Bortezomib may work in iMCD via direct inhibition of NF-kB by degrading the IkB kinase. 97 Thalidomide, an immunomodulator that inhibits TNF-a, IL-1, IL-6, IL-12, and VEGF and stimulates T cells potentially via cereblon inhibition, has demonstrated effectiveness at inducing remission, decreasing IL-6 levels, and lowering C-reactive protein in iMCD. 66,98,99 Anakinra, an IL-1 receptor antagonist, has also been reported to induce remission in a pediatric case of iMCD and in a patient who did not respond to anti-IL-6 therapy.…”

Cutaneous T‐cell lymphoma: 2011 update on diagnosis, risk‐stratification, and management

“…Furthermore, pharmacologic NF-kB inhibition in CTCL cell lines decreases NF-kB DNA binding activity, thus promoting cell death [73][74][75][76]. While the molecular mechanisms leading to constitutive NF-kB activation in CTCL are poorly understood, the observation that IKK inhibition downregulates NF-kB activity implicates upstream IKK-activating elements [74,75].…”