Abstract
Deregulated c-MYC is found in a variety of cancers where it promotes proliferation as well as apoptosis. In many hematologic malignancies, enhanced NF-κB exerts prosurvival functions. Here we investigated the role of NF-κB in mouse and human c-MYC–transformed lymphomas. The NF-κB pathway is extinguished in murine lymphoma cells, and extrinsic stimuli typically inducing NF-κB activity fail to activate this pathway. Genetic activation of the NF-κB pathway induces apoptosis in these cells, whereas inhibition of NF-κB by an IκBα superrepressor provides a selective advantage in vivo. Furthermore, in human Burkitt lymphoma cells we find that NF-κB activation induces apoptosis. NF-κB 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-κB–induced apoptosis, and persistent inactivity of NF-κB 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-κB. Our observations provide a molecular explanation for the described absence of the NF-κB signaling in Burkitt lymphoma and question the applicability of NF-κB inhibitors as candidates for treatment of this cancer.
Effect of a Hypoxic Cell Sensitizer Doranidazole on the Radiation-induced Apoptosis of Mouse L5178Y Lymphoma Cells