Key Points
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The nuclear factor-κB (NF-κB)–inhibitor of NF-κB kinase (IKK) pathway can promote the growth and survival of many solid and haematological maligancies and therefore has the potential to provide numerous targets for novel anticancer therapies.
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Most attention has focused on the development of IKKβ inhibitors, but it is now clear that IKKβ has many NF-κB-independent functions and its inhibition could result in undesired effects.
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Although it is apparent that NF-κB subunits have important roles in tumorigenesis and the response to cancer therapy, their individual contributions have not been clearly defined.
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The NF-κB response is highly pleiotropic and the consequences of its activation can be context dependent. NF-κB is not always tumour promoting and it can exhibit tumour suppressor-like activities.
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Crosstalk with tumour-suppressor proteins, such as p53, provides an important mechanism for regulating NF-κB activity and function in cancer. Tumour suppressors can inhibit the tumour-promoting activities of NF-κB subunits while facilitating their ability to suppress cancer progression.
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Understanding the regulation and function of the NF-κB subunits in cancer provides opportunities for the development of new therapies and allows the better use of existing drugs that affect NF-κB–IKK activity.
Abstract
It is only recently that the full importance of nuclear factor-κB (NF-κB) signalling to cancer development has been understood. Although much attention has focused on the upstream pathways leading to NF-κB activation, it is now becoming clear that the inhibitor of NF-κB kinases (IKKs), which regulate NF-κB activation, have many independent functions in tissue homeostasis and normal immune function that could compromise the clinical utility of IKK inhibitors. Therefore, if the NF-κB pathway is to be properly exploited as a target for both anticancer and anti-inflammatory drugs, it is appropriate to reconsider the complex roles of the individual NF-κB subunits.
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Acknowledgements
The author would like to thank D. Mann, S. Rocha, K. Campbell and all members of the N.D.P. laboratory for their critical reading of this manuscript, together with T. Gilmore, V. Tergaonkar and M. Lienhard Schmitz for helpful discussions. Research in the Perkins' laboratory is funded by Cancer Research UK (grants C1443/A12750 and C1443/A6721), the Wellcome Trust (grant 094,409), European Union FP7 'Inflacare' consortium and Leukemia and Lymphoma Research (grant 11022). The author would like to apologize to all colleagues whose work he was unable to cite in this Review.
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Glossary
- MicroRNAs
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These single-stranded RNAs are approximately 21 to 23 nucleotides in length and regulate gene expression by partial complementary base pairing to mRNAs and recruitment to the RNA-induced silencing complex to inhibit translation (and possibly increase degradation) of mRNA.
- Warburg effect
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Named after a discovery made by the German biochemist Otto Warburg in the 1920s that cancer cells predominantly use anaerobic glycolysis rather than oxidative phosphorylation, even when oxygen is abundant. As a result, pyruvate is converted to lactate instead of being oxidized by the mitochondria of cancer cells.
- Isogenically matched
-
Genetically identical.
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Perkins, N. The diverse and complex roles of NF-κB subunits in cancer. Nat Rev Cancer 12, 121–132 (2012). https://doi.org/10.1038/nrc3204
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DOI: https://doi.org/10.1038/nrc3204
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