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5.1
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Cells
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NF-κB in Cancer
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NF-κB in Cancer

A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: closed (30 June 2019) | Viewed by 80297

Special Issue Editor

Prof. Dr. Neil D. Perkins

E-Mail Website
Guest Editor
Institute for Cell and Molecular Biosciences (ICaMB), Medical School, Newcastle University, Catherine Cookson Building, Framlington Place, Newcastle upon Tyne NE2 4HH, UK
Interests: NF-κB; DNA damage; p53; CHK1; cancer; phosphorylation; cell signalling

Special Issue Information

Dear Colleagues,

It is now well established that aberrant activation of the NF-κB signalling pathway can drive cancer development and malignancy in both tumour and non-tumour cell types. Consequently, it represents an attractive drug target for the treatment of a broad range of cancer.

Under normal circumstances, NF-κB is an important regulator of the immune and inflammatory responses and comprises a family of dimeric transcription factors with common and distinct biological functions. NF-κB complexes, formed from a family of five NF-κB subunits, RelA (p65), c-Rel, RelB, NF-κB1 (p105/p50) and NF-κB2 (p100/p52), are present in all cells, but are generally held in an inactive form until induced by wide range of stimuli, including inflammatory cytokines, cell stresses such as DNA damage or hypoxia, immune receptor engagement, bacterial products and viral proteins. There are, broadly speaking, two major pathways leading to induction of NF-κB subunits. The classical (or canonical) pathway typically leads to the induction of RelA(p65) or c-Rel containing complexes and involves the degradation of IκBα in a manner dependent on IκB kinase (IKK) beta and the IKK regulatory subunit NEMO (IKKγ). The non-canonical (or alternative) pathway, involves the inducible processing of p100 to p52, leading to the induction of p52/RelB containing complexes, and is dependent on IKKα and NF-κB inducing kinase (NIK).

Aberrantly active NF-κB, induced by both the classical and non-canonical pathways, contributes to the pathology of many diseases, including cancer. In cancer, NF-κB activation only rarely results from direct mutation of the NF-κB or IKK subunits but most commonly arises either through mutation of upstream regulators leading to constitutive IKK activity or via effects of the tumour microenvironment. Its critical role in the inflammatory phenotype allows NF-κB to act as a promoter of inflammation-associated cancers. However, activation of NF-κB in tumour cells can induce many genes that regulate many of the 'Hallmarks of Cancer' and so can promote cancer progression, increased metastatic potential, tumour recurrence and therapeutic resistance in a wide range of both solid and haematological malignancies. Consequently, there is often an assumption that NF-κB is an obligate tumour promoter. However, tumour suppressor-like characteristics associated with NF-κB subunits have also been described. Understanding the complexity of NF-κB cancer biology will be required if we are to fully exploit its potential as a therapeutic target.

The aim of this special issue is to provide an overview of the broad role that NF-κB plays in cancer. This will include both its function as a driver of inflammation associated cancer and its function as an effector of oncogene induced malignancy. However, we will also cover the links between NF-κB and tumour suppressors and how these can lead to altered NF-κB behaviour in some contexts. We will cover the mechanisms leading to aberrant NF-κB in cancer, the functions of the NF-κB subunits themselves and consider, given the complexity of the pathway, the best strategies for targeting it to achieve new and improved cancer therapies.

Prof. Dr. Neil D. Perkins
Guest Editor

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Keywords

  • NF-κB
  • IKK
  • Inflammation
  • Oncogenes
  • Tumour Suppressors
  • Cancer Therapy

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Published Papers (8 papers)

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Review

21 pages, 1276 KiB  
Review
Aberrant Activation of NF-κB Signalling in Aggressive Lymphoid Malignancies
by Ruth Kennedy and Ulf Klein
Cells 2018, 7(11), 189; https://doi.org/10.3390/cells7110189 - 30 Oct 2018
Cited by 27 | Viewed by 9275
Abstract
Lymphoid malignancies frequently harbor genetic mutations leading to aberrant activation of nuclear factor-κB (NF-κB) signaling; in normal cells, this pathway has important roles in the control of cell growth, survival, stress responses, and inflammation. Malignancies with mutations in NF-κB pathway components can derive [...] Read more.
Lymphoid malignancies frequently harbor genetic mutations leading to aberrant activation of nuclear factor-κB (NF-κB) signaling; in normal cells, this pathway has important roles in the control of cell growth, survival, stress responses, and inflammation. Malignancies with mutations in NF-κB pathway components can derive from all cell stages of mature B-cell development; however, aberrant NF-κB activity is particularly prevalent in aggressive subtypes of non-Hodgkin lymphoma and myeloma. NF-κB activation is mediated by two separate pathways, the canonical and alternative pathway, and five downstream transcription factor subunits. Recent findings implicate a predominant role for distinct NF-κB pathways and subunits in certain lymphoma subtypes and myeloma; findings which are complemented by the realization that individual NF-κB subunits can have unique, non-redundant biological roles in the putative tumor precursor cells, including activated B cells, germinal center B cells and plasma cells. The knowledge gained from these studies may be exploited for the development of therapeutic strategies to inhibit aberrant NF-κB activity at the level of the transcription-factor subunits and their target genes, as global inhibition of the pathway is toxic. Here, we provide an overview on the role of aberrant NF-κB activation in aggressive lymphoid malignancies and discuss the potential importance of individual NF-κB subunits in the pathogenesis of tumor subtypes. Full article
(This article belongs to the Special Issue NF-κB in Cancer)
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Figure 1

30 pages, 2136 KiB  
Review
Inhibitory-κB Kinase (IKK) α and Nuclear Factor-κB (NFκB)-Inducing Kinase (NIK) as Anti-Cancer Drug Targets
by Andrew Paul, Joanne Edwards, Christopher Pepper and Simon Mackay
Cells 2018, 7(10), 176; https://doi.org/10.3390/cells7100176 - 20 Oct 2018
Cited by 63 | Viewed by 14389
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue NF-κB in Cancer)
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Figure 1

13 pages, 1254 KiB  
Review
Crosstalk between NF-κB and Nucleoli in the Regulation of Cellular Homeostasis
by Jingyu Chen and Lesley A. Stark
Cells 2018, 7(10), 157; https://doi.org/10.3390/cells7100157 - 5 Oct 2018
Cited by 31 | Viewed by 6224
Abstract
Nucleoli are emerging as key sensors of cellular stress and regulators of the downstream consequences on proliferation, metabolism, senescence, and apoptosis. NF-κB signalling is activated in response to a similar plethora of stresses, which leads to modulation of cell growth and death programs. [...] Read more.
Nucleoli are emerging as key sensors of cellular stress and regulators of the downstream consequences on proliferation, metabolism, senescence, and apoptosis. NF-κB signalling is activated in response to a similar plethora of stresses, which leads to modulation of cell growth and death programs. While nucleolar and NF-κB pathways are distinct, it is increasingly apparent that they converge at multiple levels. Exposure of cells to certain insults causes a specific type of nucleolar stress that is characterised by degradation of the PolI complex component, TIF-IA, and increased nucleolar size. Recent studies have shown that this atypical nucleolar stress lies upstream of cytosolic IκB degradation and NF-κB nuclear translocation. Under these stress conditions, the RelA component of NF-κB accumulates within functionally altered nucleoli to trigger a nucleophosmin dependent, apoptotic pathway. In this review, we will discuss these points of crosstalk and their relevance to anti-tumour mechanism of aspirin and small molecule CDK4 inhibitors. We will also briefly the discuss how crosstalk between nucleoli and NF-κB signalling may be more broadly relevant to the regulation of cellular homeostasis and how it may be exploited for therapeutic purpose. Full article
(This article belongs to the Special Issue NF-κB in Cancer)
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Graphical abstract

15 pages, 2199 KiB  
Review
Roles for the IKK-Related Kinases TBK1 and IKKε in Cancer
by Joel K. Durand, Qing Zhang and Albert S. Baldwin
Cells 2018, 7(9), 139; https://doi.org/10.3390/cells7090139 - 15 Sep 2018
Cited by 60 | Viewed by 9822
Abstract
While primarily studied for their roles in innate immune response, the IκB kinase (IKK)-related kinases TANK-binding kinase 1 (TBK1) and IKKε also promote the oncogenic phenotype in a variety of cancers. Additionally, several substrates of these kinases control proliferation, autophagy, cell survival, and [...] Read more.
While primarily studied for their roles in innate immune response, the IκB kinase (IKK)-related kinases TANK-binding kinase 1 (TBK1) and IKKε also promote the oncogenic phenotype in a variety of cancers. Additionally, several substrates of these kinases control proliferation, autophagy, cell survival, and cancer immune responses. Here we review the involvement of TBK1 and IKKε in controlling different cancers and in regulating responses to cancer immunotherapy. Full article
(This article belongs to the Special Issue NF-κB in Cancer)
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Graphical abstract

16 pages, 972 KiB  
Review
NFKB1 and Cancer: Friend or Foe?
by Julia Concetti and Caroline L. Wilson
Cells 2018, 7(9), 133; https://doi.org/10.3390/cells7090133 - 7 Sep 2018
Cited by 91 | Viewed by 13754
Abstract
Current evidence strongly suggests that aberrant activation of the NF-κB signalling pathway is associated with carcinogenesis. A number of key cellular processes are governed by the effectors of this pathway, including immune responses and apoptosis, both crucial in the development of cancer. Therefore, [...] Read more.
Current evidence strongly suggests that aberrant activation of the NF-κB signalling pathway is associated with carcinogenesis. A number of key cellular processes are governed by the effectors of this pathway, including immune responses and apoptosis, both crucial in the development of cancer. Therefore, it is not surprising that dysregulated and chronic NF-κB signalling can have a profound impact on cellular homeostasis. Here we discuss NFKB1 (p105/p50), one of the five subunits of NF-κB, widely implicated in carcinogenesis, in some cases driving cancer progression and in others acting as a tumour-suppressor. The complexity of the role of this subunit lies in the multiple dimeric combination possibilities as well as the different interacting co-factors, which dictate whether gene transcription is activated or repressed, in a cell and organ-specific manner. This review highlights the multiple roles of NFKB1 in the development and progression of different cancers, and the considerations to make when attempting to manipulate NF-κB as a potential cancer therapy. Full article
(This article belongs to the Special Issue NF-κB in Cancer)
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Figure 1

18 pages, 1604 KiB  
Review
NF-κB, Mesenchymal Differentiation and Glioblastoma
by Bakhtiar Yamini
Cells 2018, 7(9), 125; https://doi.org/10.3390/cells7090125 - 31 Aug 2018
Cited by 50 | Viewed by 8878
Abstract
Although glioblastoma (GBM) has always been recognized as a heterogeneous tumor, the advent of largescale molecular analysis has enabled robust categorization of this malignancy into several specific subgroups. Among the subtypes designated by expression profiling, mesenchymal tumors have been associated with an inflammatory [...] Read more.
Although glioblastoma (GBM) has always been recognized as a heterogeneous tumor, the advent of largescale molecular analysis has enabled robust categorization of this malignancy into several specific subgroups. Among the subtypes designated by expression profiling, mesenchymal tumors have been associated with an inflammatory microenvironment, increased angiogenesis, and resistance to therapy. Nuclear factor-κB (NF-κB) is a ubiquitous transcription factor that plays a prominent role in mediating many of the central features associated with mesenchymal differentiation. This review summarizes the mechanisms by which NF-κB proteins and their co-regulating partners induce the transcriptional network that underlies the mesenchymal phenotype. Moreover, both the intrinsic changes within mesenchymal GBM cells and the microenvironmental factors that modify the overall NF-κB response are detailed. Full article
(This article belongs to the Special Issue NF-κB in Cancer)
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Figure 1

20 pages, 1209 KiB  
Review
Inflammation and NF-κB Signaling in Prostate Cancer: Mechanisms and Clinical Implications
by Jens Staal and Rudi Beyaert
Cells 2018, 7(9), 122; https://doi.org/10.3390/cells7090122 - 29 Aug 2018
Cited by 71 | Viewed by 8192
Abstract
Prostate cancer is a highly prevalent form of cancer that is usually slow-developing and benign. Due to its high prevalence, it is, however, still the second most common cause of death by cancer in men in the West. The higher prevalence of prostate [...] Read more.
Prostate cancer is a highly prevalent form of cancer that is usually slow-developing and benign. Due to its high prevalence, it is, however, still the second most common cause of death by cancer in men in the West. The higher prevalence of prostate cancer in the West might be due to elevated inflammation from metabolic syndrome or associated comorbidities. NF-κB activation and many other signals associated with inflammation are known to contribute to prostate cancer malignancy. Inflammatory signals have also been associated with the development of castration resistance and resistance against other androgen depletion strategies, which is a major therapeutic challenge. Here, we review the role of inflammation and its link with androgen signaling in prostate cancer. We further describe the role of NF-κB in prostate cancer cell survival and proliferation, major NF-κB signaling pathways in prostate cancer, and the crosstalk between NF-κB and androgen receptor signaling. Several NF-κB-induced risk factors in prostate cancer and their potential for therapeutic targeting in the clinic are described. A better understanding of the inflammatory mechanisms that control the development of prostate cancer and resistance to androgen-deprivation therapy will eventually lead to novel treatment options for patients. Full article
(This article belongs to the Special Issue NF-κB in Cancer)
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Graphical abstract

34 pages, 2603 KiB  
Review
Targeting IKKβ in Cancer: Challenges and Opportunities for the Therapeutic Utilisation of IKKβ Inhibitors
by Jack A. Prescott and Simon J. Cook
Cells 2018, 7(9), 115; https://doi.org/10.3390/cells7090115 - 23 Aug 2018
Cited by 97 | Viewed by 8082
Abstract
Deregulated NF-κB signalling is implicated in the pathogenesis of numerous human inflammatory disorders and malignancies. Consequently, the NF-κB pathway has attracted attention as an attractive therapeutic target for drug discovery. As the primary, druggable mediator of canonical NF-κB signalling the IKKβ protein kinase [...] Read more.
Deregulated NF-κB signalling is implicated in the pathogenesis of numerous human inflammatory disorders and malignancies. Consequently, the NF-κB pathway has attracted attention as an attractive therapeutic target for drug discovery. As the primary, druggable mediator of canonical NF-κB signalling the IKKβ protein kinase has been the historical focus of drug development pipelines. Thousands of compounds with activity against IKKβ have been characterised, with many demonstrating promising efficacy in pre-clinical models of cancer and inflammatory disease. However, severe on-target toxicities and other safety concerns associated with systemic IKKβ inhibition have thus far prevented the clinical approval of any IKKβ inhibitors. This review will discuss the potential reasons for the lack of clinical success of IKKβ inhibitors to date, the challenges associated with their therapeutic use, realistic opportunities for their future utilisation, and the alternative strategies to inhibit NF-κB signalling that may overcome some of the limitations associated with IKKβ inhibition. Full article
(This article belongs to the Special Issue NF-κB in Cancer)
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