Inhibition of nuclear translocation of nuclear factor-kappaB despite lack of functional IkappaBalpha protein overcomes multiple defects in apoptosis signaling in human B-cell malignancies.
OBJECTIVE
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-kappaB (NF-kappaB) 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-kappaB.


METHODS
We investigated the effect of different inhibitors of NF-kappaB 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-Delta12,14-prostaglandin J(2), a known inhibitor of NF-kappaB, 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 IkappaBalpha mutational status. Surprisingly, 15-deoxy-Delta12,14-prostaglandin J(2) and the IkappaB kinase inhibitor curcumin both reduced nuclear levels of p65 in cell lines lacking IkappaBalpha, suggesting that inhibition of nuclear translocation of NF-kappaB can occur in the absence of IkappaBalpha. Finally, a synthetic peptide that specifically abrogates the assembly of the IkappaB kinase complex killed IkappaBalpha-defective cells by induction of apoptosis, paralleled by reduction of nuclear NF-kappaB.


CONCLUSIONS
These results show that molecular defects in apoptotic signaling, such as IkappaBalpha mutations, can be circumvented by targeting NF-kappaB through inhibition of the IkappaB 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 IkappaB kinases may represent an attractive therapeutic approach against these malignancies regardless of the mutational status of IkappaBalpha.
Thomas
Roman K
RK
Molecular Tumor Biology and Tumor Immunology, Department I for Internal Medicine, Center for Molecular Medicine Cologne, University of Cologne, Germany.
Sos
Martin L
ML
Zander
Thomas
T
Mani
Ozlem
O
Popov
Alexey
A
Berenbrinker
Daniel
D
Smola-Hess
Sigrun
S
Schultze
Joachim L
JL
Wolf
Jürgen
J
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002839:Chromans / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D018832:Molecular Chaperones; D009154:Mutation; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D045162:Thiazolidinediones / Q000494:pharmacology; D000077288:Troglitazone; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D002839:Chromans; D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D020672:I-kappa B Proteins; D018832:Molecular Chaperones; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D009363:Neoplasm Proteins; D045162:Thiazolidinediones; D051636:X-Linked Inhibitor of Apoptosis Protein; D000072000:NF-KappaB Inhibitor alpha; D051550:I-kappa B Kinase; D000077288:Troglitazone; D015230:Prostaglandin D2