Inhibition of Nuclear Translocation of Nuclear Factor-κB Despite Lack of Functional IκBα Protein Overcomes Multiple Defects in Apoptosis Signaling in Human B-Cell Malignancies
| Autor: | Jürgen Wolf, Özlem Mani, Roman K. Thomas, Daniel Berenbrinker, Alexey Popov, Thomas Zander, Joachim L. Schultze, Martin L. Sos, Sigrun Smola-Hess |
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| Rok vydání: | 2005 |
| Předmět: |
Cancer Research
Programmed cell death Cell Survival Active Transport Cell Nucleus HSP27 Heat-Shock Proteins Apoptosis X-Linked Inhibitor of Apoptosis Protein IκB kinase Biology Inhibitor of apoptosis Troglitazone NF-KappaB Inhibitor alpha Cell Line Tumor Humans Chromans Transcription factor Heat-Shock Proteins Cell Nucleus B-Lymphocytes Dose-Response Relationship Drug Prostaglandin D2 Kinase NF-kappa B I-kappa B Kinase Neoplasm Proteins IκBα Oncology Mutation Cancer research I-kappa B Proteins Thiazolidinediones Signal transduction Molecular Chaperones Signal Transduction |
| Zdroj: | Clinical Cancer Research. 11:8186-8194 |
| ISSN: | 1557-3265 1078-0432 |
| DOI: | 10.1158/1078-0432.ccr-05-0224 |
| Popis: | Purpose: Defective apoptosis signaling is a typical feature of classic Hodgkin's lymphoma, multiple myeloma, and activated B-cell-like diffuse large B-cell lymphoma. In these malignancies, the transcription factor nuclear factor-κB (NF-κB) is a critical mediator of apoptosis resistance and oncogenic growth, making it an attractive therapeutic target. Here, we sought to determine how to overcome apoptosis resistance experimentally in these malignancies by targeting NF-κB.Experimental Design: We investigated the effect of different inhibitors of NF-κB on classic Hodgkin's lymphoma, multiple myeloma, and activated B-cell-like diffuse large B-cell lymphoma cell lines harboring different molecular defects in apoptosis signaling both quantitatively and qualitatively.Results: The cyclopentenone prostaglandin, 15-deoxy-Δ12,14-prostaglandin J2, a known inhibitor of NF-κB, induced caspase-dependent apoptosis; it restored mitochondrial apoptotic signaling by down-regulation of X-linked inhibitor of apoptosis protein and heat shock protein 27 and led to breakdown of the mitochondrial membrane potential and, finally, cleavage of caspase-3 irrespective of IκBα mutational status. Surprisingly, 15-deoxy-Δ12,14-prostaglandin J2 and the IκB kinase inhibitor curcumin both reduced nuclear levels of p65 in cell lines lacking IκBα, suggesting that inhibition of nuclear translocation of NF-κB can occur in the absence of IκBα. Finally, a synthetic peptide that specifically abrogates the assembly of the IκB kinase complex killed IκBα-defective cells by induction of apoptosis, paralleled by reduction of nuclear NF-κB.Conclusions: These results show that molecular defects in apoptotic signaling, such as IκBα mutations, can be circumvented by targeting NF-κB through inhibition of the IκB kinase complex followed by induction of apoptosis in classic Hodgkin's lymphoma, multiple myeloma, and activated B-cell-like diffuse large B-cell lymphoma. Thus, targeting IκB kinases may represent an attractive therapeutic approach against these malignancies regardless of the mutational status of IκBα. |
| Databáze: | OpenAIRE |
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