Special Issue "NF-κB in Cancer"

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

Deadline for manuscript submissions: closed (30 June 2018)

Special Issue Editor

Guest Editor
Prof. Dr. Neil D. Perkins

Institute for Cell and Molecular Biosciences (ICaMB), Medical School, Newcastle University, Catherine Cookson Building, Framlington Place, Newcastle upon Tyne, NE2 4HH, United Kingdom
Website | E-Mail
Phone: +44 (0) 191 208 8866
Fax: +44 (0) 191 208 7424
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

Manuscript Submission Information

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Keywords

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

Published Papers (5 papers)

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Review

Open AccessReview Roles for the IKK-Related Kinases TBK1 and IKKε in Cancer
Received: 29 August 2018 / Revised: 11 September 2018 / Accepted: 13 September 2018 / Published: 15 September 2018
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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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Open AccessFeature PaperReview NFKB1 and Cancer: Friend or Foe?
Received: 15 August 2018 / Revised: 30 August 2018 / Accepted: 4 September 2018 / Published: 7 September 2018
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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,
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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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Open AccessFeature PaperReview NF-κB, Mesenchymal Differentiation and Glioblastoma
Received: 16 July 2018 / Revised: 14 August 2018 / Accepted: 30 August 2018 / Published: 31 August 2018
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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
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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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Open AccessFeature PaperReview Inflammation and NF-κB Signaling in Prostate Cancer: Mechanisms and Clinical Implications
Received: 31 July 2018 / Revised: 24 August 2018 / Accepted: 27 August 2018 / Published: 29 August 2018
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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
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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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Open AccessFeature PaperReview Targeting IKKβ in Cancer: Challenges and Opportunities for the Therapeutic Utilisation of IKKβ Inhibitors
Received: 16 July 2018 / Revised: 15 August 2018 / Accepted: 19 August 2018 / Published: 23 August 2018
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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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