This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Thomas, R. K. Articles by Wolf, J. Search for Related Content PubMed PubMed Citation Articles by Thomas, R. K. Articles by Wolf, J.

Inhibition of Nuclear Translocation of Nuclear Factor-B Despite Lack of Functional IB Protein Overcomes Multiple Defects in Apoptosis Signaling in Human B-Cell Malignancies

Authors' Affiliations: ¹ Molecular Tumor Biology and Tumor Immunology, Department I for Internal Medicine, ² Center for Molecular Medicine Cologne, and ³ Institute of Virology, University of Cologne, Cologne, Germany

Requests for reprints: Jürgen Wolf, Molecular Tumor Biology and Tumor Immunology, Department I for Internal Medicine, University of Cologne, Joseph-Stelzmann-Str. 9, 50931 Cologne, Germany. E-mail: Juergen.Wolf{at}medizin.uni-koeln.de.

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-B (NF-B) 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-B.

Experimental Design: We investigated the effect of different inhibitors of NF-B 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-12,14-prostaglandin J₂, a known inhibitor of NF-B, 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 IB mutational status. Surprisingly, 15-deoxy-12,14-prostaglandin J₂ and the IB kinase inhibitor curcumin both reduced nuclear levels of p65 in cell lines lacking IB, suggesting that inhibition of nuclear translocation of NF-B can occur in the absence of IB. Finally, a synthetic peptide that specifically abrogates the assembly of the IB kinase complex killed IB-defective cells by induction of apoptosis, paralleled by reduction of nuclear NF-B.

Conclusions: These results show that molecular defects in apoptotic signaling, such as IB mutations, can be circumvented by targeting NF-B through inhibition of the IB 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 IB kinases may represent an attractive therapeutic approach against these malignancies regardless of the mutational status of IB.

This article has been cited by other articles:

				H. Kashkar, A. Deggerich, J.-M. Seeger, B. Yazdanpanah, K. Wiegmann, D. Haubert, C. Pongratz, and M. Kronke NF-{kappa}B-independent down-regulation of XIAP by bortezomib sensitizes HL B cells against cytotoxic drugs Blood, May 1, 2007; 109(9): 3982 - 3988. [Abstract] [Full Text] [PDF]