Abstract
The transcription factor NF-κB is a key player in inflammation, cancer development, and progression. NF-κB stimulates cell proliferation, prevents apoptosis, and could promote tumor angiogenesis as well as metastasis. Extending the commonly accepted role of NF-κB in cancer formation and progression, different NF-κB subunits have been shown to be active and of particular importance in distinct types of cancer. Here, we summarize overexpression data of the NF-κB 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 κB kinases (IKK), in different human cancers, assessed by database mining. These data argue against a universal mechanism of cancer-mediated activation of NF-κB, and suggest a much more elaborated mode of NF-κB regulation, indicating a tumor type-specific upregulation of the NF-κB subunits. We further discuss recent findings showing the diverse roles of NF-κB 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-κB RELB signaling is described to be mostly present in hematological cancers, solid cancers reveal constitutive canonical NF-κB RELA or c-REL activity. Providing a linkage to cancer therapy, we discuss the recently described pivotal role of NF-κB 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-κB subunits for cancer treatment.
Highlights
The transcription factor NF-κB is a key player in inflammation, cancer development, and progression
We will discuss the current literature depicting the roles of different NF-κB subunits, their autoregulation, and specific transcriptional activity in cancer and outline how particular subunits and upstream kinases contribute to cancer progression
NF-κB might be considered as a major factor in cancer development and progression, distinct NF-κB subunits seem to be active in different kinds of cancer
Summary
The transcription factor nuclear factor “kappa-light-chain-enhancer” of activated B-cells (NF-κB) [1,2] plays a key role in a broad range of cellular processes like cell growth, apoptosis, inflammation, learning, and memory as well as immunity [3,4]. The NF-κB family is composed of five subunits, namely, RELA (p65), RELB, c-REL, p50, and p52 (Figure 1A), all comprising a conserved REL homology domain (RHD) near the N-terminus. Inactive NF-κB dimers are localized within the cytoplasm, since the NLS (nuclear localization signal) within the RHD is masked by IκBs. During canonical NF-κB signaling, binding of ligands such as cytokines, growth factors, or lipopolysaccharides to their respective receptors (see below, Section 2) leads to the phosphorylation of the IκB kinase (IKK) complex comprised of IKK1/IKK2. The p52/RELB heterodimer is able to enter the nucleus and activate specific target genes via binding to selective κB sites. Both the canonical and the non-canonical pathway have been described to be closely linked to cancer formation and progression [15] (Figure 1B, see Section 2). Tyrosine kinase-dependent NF-κB activation, were likewise described to promote cancer [16]
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