Next Article in Journal
Targeting DNA Binding for NF-κB as an Anticancer Approach in Hepatocellular Carcinoma
Next Article in Special Issue
Aberrant Activation of NF-κB Signalling in Aggressive Lymphoid Malignancies
Previous Article in Journal
Iron Depletion Affects Genes Encoding Mitochondrial Electron Transport Chain and Genes of Non­Oxidative Metabolism, Pyruvate Kinase and Lactate Dehydrogenase, in Primary Human Cardiac Myocytes Cultured upon Mechanical Stretch
Previous Article in Special Issue
Crosstalk between NF-κB and Nucleoli in the Regulation of Cellular Homeostasis
Article Menu
Issue 10 (October) cover image

Export Article

Open AccessReview
Cells 2018, 7(10), 176; https://doi.org/10.3390/cells7100176

Inhibitory-κB Kinase (IKK) α and Nuclear Factor-κB (NFκB)-Inducing Kinase (NIK) as Anti-Cancer Drug Targets

1
Strathclyde Institute of Pharmacy and Biomedical Sciences, 161 Cathedral Street, University of Strathclyde, Glasgow G4 0NR, UK
2
Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1QH, UK
3
Brighton and Sussex Medical School, University of Sussex, Brighton BN1 9PX, U.K.
*
Author to whom correspondence should be addressed.
Received: 20 September 2018 / Revised: 15 October 2018 / Accepted: 17 October 2018 / Published: 20 October 2018
(This article belongs to the Special Issue NF-κB in Cancer)
Full-Text   |   PDF [2136 KB, uploaded 22 October 2018]   |  

Abstract

The cellular kinases inhibitory-κB kinase (IKK) α and Nuclear Factor-κB (NF-κB)-inducing kinase (NIK) are well recognised as key central regulators and drivers of the non-canonical NF-κB cascade and as such dictate the initiation and development of defined transcriptional responses associated with the liberation of p52-RelB and p52-p52 NF-κB dimer complexes. Whilst these kinases and downstream NF-κB complexes transduce pro-inflammatory and growth stimulating signals that contribute to major cellular processes, they also play a key role in the pathogenesis of a number of inflammatory-based conditions and diverse cancer types, which for the latter may be a result of background mutational status. IKKα and NIK, therefore, represent attractive targets for pharmacological intervention. Here, specifically in the cancer setting, we reflect on the potential pathophysiological role(s) of each of these kinases, their associated downstream signalling outcomes and the stimulatory and mutational mechanisms leading to their increased activation. We also consider the downstream coordination of transcriptional events and phenotypic outcomes illustrative of key cancer ‘Hallmarks’ that are now increasingly perceived to be due to the coordinated recruitment of both NF-κB-dependent as well as NF-κB–independent signalling. Furthermore, as these kinases regulate the transition from hormone-dependent to hormone-independent growth in defined tumour subsets, potential tumour reactivation and major cytokine and chemokine species that may have significant bearing upon tumour-stromal communication and tumour microenvironment it reiterates their potential to be drug targets. Therefore, with the emergence of small molecule kinase inhibitors targeting each of these kinases, we consider medicinal chemistry efforts to date and those evolving that may contribute to the development of viable pharmacological intervention strategies to target a variety of tumour types. View Full-Text
Keywords: inhibitory-κB kinase (IKK) α; Nuclear Factor-κB (NF-κB); NF-κB-inducing kinase (NIK); cancer; inflammation; small molecule kinase inhibitor inhibitory-κB kinase (IKK) α; Nuclear Factor-κB (NF-κB); NF-κB-inducing kinase (NIK); cancer; inflammation; small molecule kinase inhibitor
Figures

Figure 1

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
SciFeed

Share & Cite This Article

MDPI and ACS Style

Paul, A.; Edwards, J.; Pepper, C.; Mackay, S. Inhibitory-κB Kinase (IKK) α and Nuclear Factor-κB (NFκB)-Inducing Kinase (NIK) as Anti-Cancer Drug Targets. Cells 2018, 7, 176.

Show more citation formats Show less citations formats

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Related Articles

Article Metrics

Article Access Statistics

1

Comments

[Return to top]
Cells EISSN 2073-4409 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top