The IKK2/NF-{kappa}B pathway suppresses MYC-induced lymphomagenesis.
Deregulated c-MYC is found in a variety of cancers where it promotes proliferation as well as apoptosis. In many hematologic malignancies, enhanced NF-kappaB exerts prosurvival functions. Here we investigated the role of NF-kappaB in mouse and human c-MYC-transformed lymphomas. The NF-kappaB pathway is extinguished in murine lymphoma cells, and extrinsic stimuli typically inducing NF-kappaB activity fail to activate this pathway. Genetic activation of the NF-kappaB pathway induces apoptosis in these cells, whereas inhibition of NF-kappaB by an IkappaBalpha superrepressor provides a selective advantage in vivo. Furthermore, in human Burkitt lymphoma cells we find that NF-kappaB activation induces apoptosis. NF-kappaB up-regulates Fas and predisposes to Fas-induced cell death, which is caspase-8 mediated and can be prevented by CFLAR overexpression. We conclude that c-MYC overexpression sensitizes cells to NF-kappaB-induced apoptosis, and persistent inactivity of NF-kappaB signaling is a prerequisite for MYC-mediated tumorigenesis. We could also show that low immunogenicity and Fas insensitivity of MYC-driven lymphoma cells are reversed by activation of NF-kappaB. Our observations provide a molecular explanation for the described absence of the NF-kappaB signaling in Burkitt lymphoma and question the applicability of NF-kappaB inhibitors as candidates for treatment of this cancer.
Klapproth
Kay
K
Institute of Physiological Chemistry, University of Ulm, Germany.
Sander
Sandrine
S
Marinkovic
Dragan
D
Baumann
Bernd
B
Wirth
Thomas
T
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002051:Burkitt Lymphoma / Q000378:metabolism / Q000473:pathology*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D024202:Electrophoretic Mobility Shift Assay; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051550:I-kappa B Kinase / Q000502:physiology*; D016393:Lymphoma, B-Cell / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D016328:NF-kappa B / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000502:physiology*
D016328:NF-kappa B; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; D051550:I-kappa B Kinase; D020169:Caspases