Oncogenic activation of NF-kappaB.
Recent genetic evidence has established a pathogenetic role for NF-kappaB signaling in cancer. NF-kappaB signaling is engaged transiently when normal B lymphocytes respond to antigens, but lymphomas derived from these cells accumulate genetic lesions that constitutively activate NF-kappaB signaling. Many genetic aberrations in lymphomas alter CARD11, MALT1, or BCL10, which constitute a signaling complex that is intermediate between the B-cell receptor and IkappaB kinase. The activated B-cell-like subtype of diffuse large B-cell lymphoma activates NF-kappaB by a variety of mechanisms including oncogenic mutations in CARD11 and a chronic active form of B-cell receptor signaling. Normal plasma cells activate NF-kappaB in response to ligands in the bone marrow microenvironment, but their malignant counterpart, multiple myeloma, sustains a variety of genetic hits that stabilize the kinase NIK, leading to constitutive activation of the classical and alternative NF-kappaB pathways. Various oncogenic abnormalities in epithelial cancers, including mutant K-ras, engage unconventional IkappaB kinases to activate NF-kappaB. Inhibition of constitutive NF-kappaB signaling in each of these cancer types induces apoptosis, providing a rationale for the development of NF-kappaB pathway inhibitors for the treatment of cancer.
Metabolism Branch, Center for Cancer Research, National Cancer Institute/NIH, Bethesda, MD 20892-8322, USA. lstaudt@mail.nih.gov
Louis M
LM
Staudt
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction
D000970:Antineoplastic Agents; D016328:NF-kappa B