The NF-kappaB activation pathways, emerging molecular targets for cancer prevention and therapy

Abstract

Importance of the field: Nuclear factor kappa B (NF-kappaB) is activated by a variety of cancer-promoting agents. The reciprocal activation between NF-kappaB and inflammatory cytokines makes NF-kappaB important for inflammation-associated cancer development. Both the constitutive and anticancer therapeutic-induced NF-kappaB activation blunts the anticancer activities of the therapy. Elucidating the roles of NF-kappaB in cancer facilitates developing approaches for cancer prevention and therapy.

Areas covered in this review: By searching PubMed, we summarize the progress of studies on NF-kappaB in carcinogenesis and cancer cells' drug resistance in recent 10 years.

What the reader will gain: The mechanisms by which NF-kappaB activation pathways are activated; the roles and mechanisms of NF-kappaB in cell survival and proliferation, and in carcinogenesis and cancer cells' response to therapy; recent development of NF-kappaB-modulating means and their application in cancer prevention and therapy.

Take home message: NF-kappaB is involved in cancer development, modulating NF-kappaB activation pathways has important implications in cancer prevention and therapy. Due to the complexity of NF-kappaB roles in different cancers, careful evaluation of NF-kappaB's in each cancer type is crucial in this regard. More cancer cell-specific NF-kappaB inhibiting means are desired for improving anticancer efficacy and reducing systemic toxicity.

Figure 1. The NF-κB activation pathways

TNF-α is shown as a representative inducer of the canonical pathway. In this pathway, TNF receptor 1 recruits and activates IKK to form a signaling complex through TNF receptor associated death domain (TRADD), RIP, and TRAF2. IKK then phosphorylates IκB, which leads to IκB ubiquitination and degradation in the proteasome. Subsequently, the NF-κB complex (p65/p50) migrates to the nucleus and activates gene transcription. In the non-canonical pathway (represented by CD40L), NIK-mediated IKKα activation triggers the processing of p100 to create p52. Then the NF-κB complex (p52/RelB) moves to the nucleus to activate gene transcription. In the atypical pathway such as that activated by UV, IKK-independent mechanisms are involved in IκB phosphorylation.