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Review
. 2010 Jan;14(1):45-55.
doi: 10.1517/14728220903431069.

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

Yong Lin  1 , Lang Bai, Wenjie Chen, Shanling Xu
Affiliations
Review

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

Yong Lin et al. Expert Opin Ther Targets. 2010 Jan.

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.

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Figures

Figure 1
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.
See this image and copyright information in PMC

References

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    1. Devin A, Cook A, Lin Y, et al. The distinct roles of TRAF2 and RIP in IKK activation by TNF-R1: TRAF2 recruits IKK to TNF-R1 while RIP mediates IKK activation. Immunity. 2000;12(4):419–29. - PubMed
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    1. Chen ZJ. Ubiquitin signalling in the NF-κB pathway. Nat Cell Biol. 2005;7(8):758–65. - PMC - PubMed

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