Subunit-Specific Role of NF-kappa B in Cancer

The transcription factor NF-kappa B is a key player in inflammation, cancer development, and progression. NF-kappa B stimulates cell proliferation, prevents apoptosis, and could promote tumor angiogenesis as well as metastasis. Extending the commonly accepted role of NF-kappa B in cancer formation and progression, different NF-kappa B subunits have been shown to be active and of particular importance in distinct types of cancer. Here, we summarize overexpression data of the NF-kappa B subunits RELA, RELB, and c-REL (referring to the v-REL, which is the oncogene of Reticuloendotheliosis virus strain T) as well as of their upstream kinase inhibitor, namely inhibitor of B kinases (IKK), in different human cancers, assessed by database mining. These data argue against a universal mechanism of cancer-mediated activation of NF-kappa B, and suggest a much more elaborated mode of NF-kappa B regulation, indicating a tumor type-specific upregulation of the NF-kappa B subunits. We further discuss recent findings showing the diverse roles of NF-kappa B signaling in cancer development and metastasis in a subunit-specific manner, emphasizing their specific transcriptional activity and the role of autoregulation. While non-canonical NF-kappa B RELB signaling is described to be mostly present in hematological cancers, solid cancers reveal constitutive canonical NF-kappa B RELA or c-REL activity. Providing a linkage to cancer therapy, we discuss the recently described pivotal role of NF-kappa B c-REL in regulating cancer-targeting immune responses. In addition, current strategies and ongoing clinical trials are summarized, which utilize genome editing or drugs to inhibit the NF-kappa B subunits for cancer treatment.