Special Issue "Roles of NF-κB in Cancer and Their Therapeutic Approaches"

A special issue of Biomedicines (ISSN 2227-9059).

Deadline for manuscript submissions: closed (1 March 2018)

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editor

Guest Editor
Dr. Veronique Baud

1. "NF-kB, Differenciation and Cancer", Université Paris Descartes, Sorbonne Paris Cité, 75014 Paris, France
2. Faculté de Pharmacie, 4 Avenue de l'Observatoire, 75006 Paris, France
Website | E-Mail
Interests: interface between signal transduction and cancer with a focus on the alternative NF-kappaB signaling pathway, how it is regulated, and its contributions towards tumor development and resistance to conventional cancer therapies

Special Issue Information

Dear Colleagues,

Although mortality rates have declined in recent years, the majority of cancers are still difficult to treat and the medical need for better cancer treatment is evident. The current anticancer armamentarium includes many active agents that are applied across tumor types. However, most of these broadly-active anticancer drugs have a small therapeutic index and barely discriminate between malignant and normal cells. In recent years the focus has shifted to the development of rationally designed, molecularly-targeted therapy for the treatment of a specific cancer, therefore offering the promise of greater specificity coupled with reduced systemic toxicity. NF-κB transcription factor family as emerged as such a promising target for cancer therapy. This Special Issue will explore the routes from NF-κB basic research, cancer research and oncogenomics into the development of NF-κB-based cancer therapeutics and biomarkers.

We invite research and review papers in any area of the NF-κB field that are related, but not limited to, fundamental understanding of NF-κB signaling pathways, gene expression profiling, epigenetic regulation, diagnostic, prognostic and pharmacogenomic biomarkers, molecular targets driving the progression of human cancers, cancer drug development on these targets, clinical trial with new agents, and validation in animal models.

We hope that this Special Issue reflects the exciting era that we are living in with respect to the field of NF-κB and its applications in cancer research.

Dr. Véronique Baud
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomedicines is an international peer-reviewed open access quarterly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 550 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • NF-κB subunits
  • NF-κB signaling pathways
  • NF-κB related to:
    • solid tumors
    • hematological malignancies
    • oncogenomics
    • epigenetics
    • gene expression profiling
    • biomarkers
    • miRNA
    • ubiquitin-proteasome pathway
    • molecular targets
    • cancer targeted diagnosis
    • cancer targeted therapeutics
    • mechanism-based drug development
    • clinical trials
    • animal models

Related Special Issue

Published Papers (18 papers)

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Research

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Open AccessArticle Deubiquitinylase USP47 Promotes RelA Phosphorylation and Survival in Gastric Cancer Cells
Biomedicines 2018, 6(2), 62; https://doi.org/10.3390/biomedicines6020062
Received: 13 February 2018 / Revised: 11 May 2018 / Accepted: 12 May 2018 / Published: 22 May 2018
PDF Full-text (2198 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Every year, gastric cancer causes around 819,000 deaths worldwide. The incidence of gastric cancer in the western world is slowly declining, but the prognosis is unpromising. In Germany, the 5-year-survival rate is around 32%, and the average life span after diagnosis is 6
[...] Read more.
Every year, gastric cancer causes around 819,000 deaths worldwide. The incidence of gastric cancer in the western world is slowly declining, but the prognosis is unpromising. In Germany, the 5-year-survival rate is around 32%, and the average life span after diagnosis is 6 to 9 months. Therapy of gastric cancer patients comprises a gastrectomy and perioperative or adjuvant chemotherapy. However, resistance of gastric cancer cells to these agents is widespread; thus, improved chemotherapeutic approaches are required. Nuclear factor kappa B (NF-κB) transcription factors are associated with anti-apoptosis, carcinogenesis, and chemoresistance, and thus, constitute attractive targets for therapeutic intervention. In immunoblots, we show that ubiquitin specific protease 47 (USP47) promotes β-transducin repeat-containing protein (βTrCP) stability and phosphorylation of RelA. Furthermore, after knockdown of USP47 by RNA interference, we analyzed in gastric cancer cell lines metabolic activity/viability in an MTT assay, and apoptotic cell death by Annexin V staining and poly(ADP-Ribose) polymerase (PARP)-1, caspase 3, and caspase 8 cleavage, respectively. We found that USP47 contributes to cell viability and chemoresistance in NCI-N87 gastric carcinoma cells treated with etoposide and camptothecin. Inhibition of USP47 might be a suitable strategy to downregulate NF-κB activity, and to overcome chemoresistance in gastric cancer. Full article
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Review

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Open AccessReview Noncanonical NF-κB in Cancer
Biomedicines 2018, 6(2), 66; https://doi.org/10.3390/biomedicines6020066
Received: 10 May 2018 / Revised: 31 May 2018 / Accepted: 4 June 2018 / Published: 5 June 2018
Cited by 1 | PDF Full-text (1376 KB) | HTML Full-text | XML Full-text
Abstract
The NF-κB pathway is a critical regulator of immune responses and is often dysregulated in cancer. Two NF-κB pathways have been described to mediate these responses, the canonical and the noncanonical. While understudied compared to the canonical NF-κB pathway, noncanonical NF-κB and its
[...] Read more.
The NF-κB pathway is a critical regulator of immune responses and is often dysregulated in cancer. Two NF-κB pathways have been described to mediate these responses, the canonical and the noncanonical. While understudied compared to the canonical NF-κB pathway, noncanonical NF-κB and its components have been shown to have effects, usually protumorigenic, in many different cancer types. Here, we review noncanonical NF-κB pathways and discuss its important roles in promoting cancer. We also discuss alternative NF-κB-independent functions of some the components of noncanonical NF-κB signaling. Finally, we discuss important crosstalk between canonical and noncanonical signaling, which blurs the two pathways, indicating that understanding the full picture of NF-κB regulation is critical to deciphering how this broad pathway promotes oncogenesis. Full article
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Open AccessReview The NF-κB Activating Pathways in Multiple Myeloma
Biomedicines 2018, 6(2), 59; https://doi.org/10.3390/biomedicines6020059
Received: 12 March 2018 / Revised: 14 May 2018 / Accepted: 14 May 2018 / Published: 16 May 2018
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Abstract
Multiple myeloma(MM), an incurable plasma cell cancer, represents the second most prevalent hematological malignancy. Deregulated activity of the nuclear factor kappaB (NF-κB) family of transcription factors has been implicated in the pathogenesis of multiple myeloma. Tumor microenvironment-derived cytokines and cancer-associated genetic mutations signal
[...] Read more.
Multiple myeloma(MM), an incurable plasma cell cancer, represents the second most prevalent hematological malignancy. Deregulated activity of the nuclear factor kappaB (NF-κB) family of transcription factors has been implicated in the pathogenesis of multiple myeloma. Tumor microenvironment-derived cytokines and cancer-associated genetic mutations signal through the canonical as well as the non-canonical arms to activate the NF-κB system in myeloma cells. In fact, frequent engagement of both the NF-κB pathways constitutes a distinguishing characteristic of myeloma. In turn, NF-κB signaling promotes proliferation, survival and drug-resistance of myeloma cells. In this review article, we catalog NF-κB activating genetic mutations and microenvironmental cues associated with multiple myeloma. We then describe how the individual canonical and non-canonical pathways transduce signals and contribute towards NF-κB -driven gene-expressions in healthy and malignant cells. Furthermore, we discuss signaling crosstalk between concomitantly triggered NF-κB pathways, and its plausible implication for anomalous NF-κB activation and NF-κB driven pro-survival gene-expressions in multiple myeloma. Finally, we propose that mechanistic understanding of NF-κB deregulations may provide for improved therapeutic and prognostic tools in multiple myeloma. Full article
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Open AccessReview The Crosstalk of Endoplasmic Reticulum (ER) Stress Pathways with NF-κB: Complex Mechanisms Relevant for Cancer, Inflammation and Infection
Biomedicines 2018, 6(2), 58; https://doi.org/10.3390/biomedicines6020058
Received: 21 April 2018 / Revised: 8 May 2018 / Accepted: 11 May 2018 / Published: 16 May 2018
Cited by 1 | PDF Full-text (1928 KB) | HTML Full-text | XML Full-text
Abstract
Stressful conditions occuring during cancer, inflammation or infection activate adaptive responses that are controlled by the unfolded protein response (UPR) and the nuclear factor of kappa light polypeptide gene enhancer in B-cells (NF-κB) signaling pathway. These systems can be triggered by chemical compounds
[...] Read more.
Stressful conditions occuring during cancer, inflammation or infection activate adaptive responses that are controlled by the unfolded protein response (UPR) and the nuclear factor of kappa light polypeptide gene enhancer in B-cells (NF-κB) signaling pathway. These systems can be triggered by chemical compounds but also by cytokines, toll-like receptor ligands, nucleic acids, lipids, bacteria and viruses. Despite representing unique signaling cascades, new data indicate that the UPR and NF-κB pathways converge within the nucleus through ten major transcription factors (TFs), namely activating transcription factor (ATF)4, ATF3, CCAAT/enhancer-binding protein (CEBP) homologous protein (CHOP), X-box-binding protein (XBP)1, ATF6α and the five NF-κB subunits. The combinatorial occupancy of numerous genomic regions (enhancers and promoters) coordinates the transcriptional activation or repression of hundreds of genes that collectively determine the balance between metabolic and inflammatory phenotypes and the extent of apoptosis and autophagy or repair of cell damage and survival. Here, we also discuss results from genetic experiments and chemical activators of endoplasmic reticulum (ER) stress that suggest a link to the cytosolic inhibitor of NF-κB (IκB)α degradation pathway. These data show that the UPR affects this major control point of NF-κB activation through several mechanisms. Taken together, available evidence indicates that the UPR and NF-κB interact at multiple levels. This crosstalk provides ample opportunities to fine-tune cellular stress responses and could also be exploited therapeutically in the future. Full article
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Open AccessReview NF-κB, the Importance of Being Dynamic: Role and Insights in Cancer
Biomedicines 2018, 6(2), 45; https://doi.org/10.3390/biomedicines6020045
Received: 14 March 2018 / Revised: 11 April 2018 / Accepted: 13 April 2018 / Published: 17 April 2018
Cited by 3 | PDF Full-text (2017 KB) | HTML Full-text | XML Full-text
Abstract
In this review, we aim at describing the results obtained in the past years on dynamics features defining NF-κB regulatory functions, as we believe that these developments might have a transformative effect on the way in which NF-κB involvement in cancer is studied.
[...] Read more.
In this review, we aim at describing the results obtained in the past years on dynamics features defining NF-κB regulatory functions, as we believe that these developments might have a transformative effect on the way in which NF-κB involvement in cancer is studied. We will also describe technical aspects of the studies performed in this context, including the use of different cellular models, culture conditions, microscopy approaches and quantification of the imaging data, balancing their strengths and limitations and pointing out to common features and to some open questions. Our emphasis in the methodology will allow a critical overview of literature and will show how these cutting-edge approaches can contribute to shed light on the involvement of NF-κB deregulation in tumour onset and progression. We hypothesize that this “dynamic point of view” can be fruitfully applied to untangle the complex relationship between NF-κB and cancer and to find new targets to restrain cancer growth. Full article
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Open AccessReview Subunit-Specific Role of NF-κB in Cancer
Biomedicines 2018, 6(2), 44; https://doi.org/10.3390/biomedicines6020044
Received: 1 March 2018 / Revised: 11 April 2018 / Accepted: 12 April 2018 / Published: 17 April 2018
Cited by 7 | PDF Full-text (9150 KB) | HTML Full-text | XML Full-text
Abstract
The transcription factor NF-κB is a key player in inflammation, cancer development, and progression. NF-κB stimulates cell proliferation, prevents apoptosis, and could promote tumor angiogenesis as well as metastasis. Extending the commonly accepted role of NF-κB in cancer formation and progression, different NF-κB
[...] Read more.
The transcription factor NF-κB is a key player in inflammation, cancer development, and progression. NF-κB stimulates cell proliferation, prevents apoptosis, and could promote tumor angiogenesis as well as metastasis. Extending the commonly accepted role of NF-κB in cancer formation and progression, different NF-κB subunits have been shown to be active and of particular importance in distinct types of cancer. Here, we summarize overexpression data of the NF-κB subunits RELA, RELB, and c-REL (referring to the v-REL, which is the oncogene of Reticuloendotheliosis virus strain T) as well as of their upstream kinase inhibitor, namely inhibitor of κB kinases (IKK), in different human cancers, assessed by database mining. These data argue against a universal mechanism of cancer-mediated activation of NF-κB, and suggest a much more elaborated mode of NF-κB regulation, indicating a tumor type-specific upregulation of the NF-κB subunits. We further discuss recent findings showing the diverse roles of NF-κB signaling in cancer development and metastasis in a subunit-specific manner, emphasizing their specific transcriptional activity and the role of autoregulation. While non-canonical NF-κB RELB signaling is described to be mostly present in hematological cancers, solid cancers reveal constitutive canonical NF-κB RELA or c-REL activity. Providing a linkage to cancer therapy, we discuss the recently described pivotal role of NF-κB c-REL in regulating cancer-targeting immune responses. In addition, current strategies and ongoing clinical trials are summarized, which utilize genome editing or drugs to inhibit the NF-κB subunits for cancer treatment. Full article
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Open AccessReview The Many Roles of Ubiquitin in NF-κB Signaling
Biomedicines 2018, 6(2), 43; https://doi.org/10.3390/biomedicines6020043
Received: 15 March 2018 / Revised: 31 March 2018 / Accepted: 2 April 2018 / Published: 10 April 2018
Cited by 2 | PDF Full-text (18194 KB) | HTML Full-text | XML Full-text
Abstract
The nuclear factor κB (NF-κB) signaling pathway ubiquitously controls cell growth and survival in basic conditions as well as rapid resetting of cellular functions following environment changes or pathogenic insults. Moreover, its deregulation is frequently observed during cell transformation, chronic inflammation or autoimmunity.
[...] Read more.
The nuclear factor κB (NF-κB) signaling pathway ubiquitously controls cell growth and survival in basic conditions as well as rapid resetting of cellular functions following environment changes or pathogenic insults. Moreover, its deregulation is frequently observed during cell transformation, chronic inflammation or autoimmunity. Understanding how it is properly regulated therefore is a prerequisite to managing these adverse situations. Over the last years evidence has accumulated showing that ubiquitination is a key process in NF-κB activation and its resolution. Here, we examine the various functions of ubiquitin in NF-κB signaling and more specifically, how it controls signal transduction at the molecular level and impacts in vivo on NF-κB regulated cellular processes. Full article
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Open AccessReview Roles of NF-κB Signaling in the Regulation of miRNAs Impacting on Inflammation in Cancer
Biomedicines 2018, 6(2), 40; https://doi.org/10.3390/biomedicines6020040
Received: 5 March 2018 / Revised: 26 March 2018 / Accepted: 27 March 2018 / Published: 30 March 2018
Cited by 3 | PDF Full-text (2399 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The NF-κB family of transcription factors regulate the expression of genes encoding proteins and microRNAs (miRNA, miR) precursors that may either positively or negatively regulate a variety of biological processes such as cell cycle progression, cell survival, and cell differentiation. The NF-κB-miRNA transcriptional
[...] Read more.
The NF-κB family of transcription factors regulate the expression of genes encoding proteins and microRNAs (miRNA, miR) precursors that may either positively or negatively regulate a variety of biological processes such as cell cycle progression, cell survival, and cell differentiation. The NF-κB-miRNA transcriptional regulatory network has been implicated in the regulation of proinflammatory, immune, and stress-like responses. Gene regulation by miRNAs has emerged as an additional epigenetic mechanism at the post-transcriptional level. The expression of miRNAs can be regulated by specific transcription factors (TFs), including the NF-κB TF family, and vice versa. The interplay between TFs and miRNAs creates positive or negative feedback loops and also regulatory networks, which can control cell fate. In the current review, we discuss the impact of NF-κB-miRNA interplay and feedback loops and networks impacting on inflammation in cancer. We provide several paradigms of specific NF-κB-miRNA networks that can regulate inflammation linked to cancer. For example, the NF-κB-miR-146 and NF-κB-miR-155 networks fine-tune the activity, intensity, and duration of inflammation, while the NF-κB-miR-21 and NF-κB-miR-181b-1 amplifying loops link inflammation to cancer; and p53- or NF-κB-regulated miRNAs interconnect these pathways and may shift the balance to cancer development or tumor suppression. The availability of genomic data may be useful to verify and find novel interactions, and provide a catalogue of 162 miRNAs targeting and 40 miRNAs possibly regulated by NF-κB. We propose that studying active TF-miRNA transcriptional regulatory networks such as NF-κB-miRNA networks in specific cancer types can contribute to our further understanding of the regulatory interplay between inflammation and cancer, and also perhaps lead to the development of pharmacologically novel therapeutic approaches to combat cancer. Full article
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Open AccessFeature PaperReview NF-κB Activation in Lymphoid Malignancies: Genetics, Signaling, and Targeted Therapy
Biomedicines 2018, 6(2), 38; https://doi.org/10.3390/biomedicines6020038
Received: 5 March 2018 / Revised: 20 March 2018 / Accepted: 22 March 2018 / Published: 26 March 2018
Cited by 2 | PDF Full-text (50756 KB) | HTML Full-text | XML Full-text
Abstract
The NF-κB transcription factor family plays a crucial role in lymphocyte proliferation and survival. Consequently, aberrant NF-κB activation has been described in a variety of lymphoid malignancies, including diffuse large B-cell lymphoma, Hodgkin lymphoma, and adult T-cell leukemia. Several factors, such as persistent
[...] Read more.
The NF-κB transcription factor family plays a crucial role in lymphocyte proliferation and survival. Consequently, aberrant NF-κB activation has been described in a variety of lymphoid malignancies, including diffuse large B-cell lymphoma, Hodgkin lymphoma, and adult T-cell leukemia. Several factors, such as persistent infections (e.g., with Helicobacter pylori), the pro-inflammatory microenvironment of the cancer, self-reactive immune receptors as well as genetic lesions altering the function of key signaling effectors, contribute to constitutive NF-κB activity in these malignancies. In this review, we will discuss the molecular consequences of recurrent genetic lesions affecting key regulators of NF-κB signaling. We will particularly focus on the oncogenic mechanisms by which these alterations drive deregulated NF-κB activity and thus promote the growth and survival of the malignant cells. As the concept of a targeted therapy based on the mutational status of the malignancy has been supported by several recent preclinical and clinical studies, further insight in the function of NF-κB modulators and in the molecular mechanisms governing aberrant NF-κB activation observed in lymphoid malignancies might lead to the development of additional treatment strategies and thus improve lymphoma therapy. Full article
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Open AccessReview The Direct and Indirect Roles of NF-κB in Cancer: Lessons from Oncogenic Fusion Proteins and Knock-in Mice
Biomedicines 2018, 6(1), 36; https://doi.org/10.3390/biomedicines6010036
Received: 28 February 2018 / Revised: 16 March 2018 / Accepted: 17 March 2018 / Published: 19 March 2018
Cited by 3 | PDF Full-text (1742 KB) | HTML Full-text | XML Full-text | Correction
Abstract
NF-κB signaling pathways play an important role in the regulation of cellular immune and stress responses. Aberrant NF-κB activity has been implicated in almost all the steps of cancer development and many of the direct and indirect contributions of this transcription factor system
[...] Read more.
NF-κB signaling pathways play an important role in the regulation of cellular immune and stress responses. Aberrant NF-κB activity has been implicated in almost all the steps of cancer development and many of the direct and indirect contributions of this transcription factor system for oncogenesis were revealed in the recent years. The indirect contributions affect almost all hallmarks and enabling characteristics of cancer, but NF-κB can either promote or antagonize these tumor-supportive functions, thus prohibiting global NF-κB inhibition. The direct effects are due to mutations of members of the NF-κB system itself. These mutations typically occur in upstream components that lead to the activation of NF-κB together with further oncogenesis-promoting signaling pathways. In contrast, mutations of the downstream components, such as the DNA-binding subunits, contribute to oncogenic transformation by affecting NF-κB-driven transcriptional output programs. Here, we discuss the features of recently identified oncogenic RelA fusion proteins and the characterization of pathways that are regulating the transcriptional activity of NF-κB by regulatory phosphorylations. As NF-κB’s central role in human physiology prohibits its global inhibition, these auxiliary or cell type-specific NF-κB regulating pathways are potential therapeutic targets. Full article
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Open AccessReview BET Family Protein BRD4: An Emerging Actor in NFκB Signaling in Inflammation and Cancer
Biomedicines 2018, 6(1), 16; https://doi.org/10.3390/biomedicines6010016
Received: 16 October 2017 / Revised: 31 January 2018 / Accepted: 1 February 2018 / Published: 6 February 2018
Cited by 2 | PDF Full-text (824 KB) | HTML Full-text | XML Full-text
Abstract
NFκB (Nuclear Factor-κ-light-chain-enhancer of activated B cells) signaling elicits global transcriptional changes by activating cognate promoters and through genome-wide remodeling of cognate regulatory elements called “super enhancers”. BET (Bromodomain and Extra-Terminal domain) protein family inhibitor studies have implicated BET protein member
[...] Read more.
NFκB (Nuclear Factor-κ-light-chain-enhancer of activated B cells) signaling elicits global transcriptional changes by activating cognate promoters and through genome-wide remodeling of cognate regulatory elements called “super enhancers”. BET (Bromodomain and Extra-Terminal domain) protein family inhibitor studies have implicated BET protein member BRD4 and possibly other BET proteins in NFκB-dependent promoter and super-enhancer modulation. Members of the BET protein family are known to bind acetylated chromatin to facilitate access by transcriptional regulators to chromatin, as well as to assist the activity of transcription elongation complexes via CDK9/pTEFb. BET family member BRD4 has been shown to bind non-histone proteins and modulate their activity. One such protein is RELA, the NFκB co-activator. Specifically, BRD4 binds acetylated RELA, which increases its transcriptional transactivation activity and stability in the nucleus. In aggregate, this establishes an intimate link between NFκB and BET signaling, at least via BRD4. The present review provides a brief overview of the structure and function of BET family proteins and then examines the connections between NFκB and BRD4 signaling, using the inflammatory response and cancer cell signaling as study models. We also discuss the potential of BET inhibitors for relief of aberrant NFκB signaling in cancer, focusing on non-histone, acetyl-lysine binding functions. Full article
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Open AccessReview Unlocking the NF-κB Conundrum: Embracing Complexity to Achieve Specificity
Biomedicines 2017, 5(3), 50; https://doi.org/10.3390/biomedicines5030050
Received: 30 June 2017 / Revised: 4 August 2017 / Accepted: 10 August 2017 / Published: 22 August 2017
Cited by 9 | PDF Full-text (3919 KB) | HTML Full-text | XML Full-text
Abstract
Transcription factors of the nuclear factor κB (NF-κB) family are central coordinating regulators of the host defence responses to stress, injury and infection. Aberrant NF-κB activation also contributes to the pathogenesis of some of the most common current threats to global human health,
[...] Read more.
Transcription factors of the nuclear factor κB (NF-κB) family are central coordinating regulators of the host defence responses to stress, injury and infection. Aberrant NF-κB activation also contributes to the pathogenesis of some of the most common current threats to global human health, including chronic inflammatory diseases, autoimmune disorders, diabetes, vascular diseases and the majority of cancers. Accordingly, the NF-κB pathway is widely considered an attractive therapeutic target in a broad range of malignant and non-malignant diseases. Yet, despite the aggressive efforts by the pharmaceutical industry to develop a specific NF-κB inhibitor, none has been clinically approved, due to the dose-limiting toxicities associated with the global suppression of NF-κB. In this review, we summarise the main strategies historically adopted to therapeutically target the NF-κB pathway with an emphasis on oncology, and some of the emerging strategies and newer agents being developed to pharmacologically inhibit this pathway. Full article
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Open AccessReview Aspirin Prevention of Colorectal Cancer: Focus on NF-κB Signalling and the Nucleolus
Biomedicines 2017, 5(3), 43; https://doi.org/10.3390/biomedicines5030043
Received: 20 June 2017 / Revised: 7 July 2017 / Accepted: 13 July 2017 / Published: 18 July 2017
Cited by 3 | PDF Full-text (1130 KB) | HTML Full-text | XML Full-text
Abstract
Overwhelming evidence indicates that aspirin and related non-steroidal anti-inflammatory drugs (NSAIDs) have anti-tumour activity and the potential to prevent cancer, particularly colorectal cancer. However, the mechanisms underlying this effect remain hypothetical. Dysregulation of the nuclear factor-kappaB (NF-κB) transcription factor is a common event
[...] Read more.
Overwhelming evidence indicates that aspirin and related non-steroidal anti-inflammatory drugs (NSAIDs) have anti-tumour activity and the potential to prevent cancer, particularly colorectal cancer. However, the mechanisms underlying this effect remain hypothetical. Dysregulation of the nuclear factor-kappaB (NF-κB) transcription factor is a common event in many cancer types which contributes to tumour initiation and progression by driving expression of pro-proliferative/anti-apoptotic genes. In this review, we will focus on the current knowledge regarding NSAID effects on the NF-κB signalling pathway in pre-cancerous and cancerous lesions, and the evidence that these effects contribute to the anti-tumour activity of the agents. The nuclear organelle, the nucleolus, is emerging as a central regulator of transcription factor activity and cell growth and death. Nucleolar function is dysregulated in the majority of cancers which promotes cancer growth through direct and indirect mechanisms. Hence, this organelle is emerging as a promising target for novel therapeutic agents. Here, we will also discuss evidence for crosstalk between the NF-κB pathway and nucleoli, the role that this cross-talk has in the anti-tumour effects of NSAIDs and ways forward to exploit this crosstalk for therapeutic purpose. Full article
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Open AccessFeature PaperReview NF-κB Signalling in Glioblastoma
Biomedicines 2017, 5(2), 29; https://doi.org/10.3390/biomedicines5020029
Received: 3 April 2017 / Revised: 6 June 2017 / Accepted: 7 June 2017 / Published: 9 June 2017
Cited by 3 | PDF Full-text (264 KB) | HTML Full-text | XML Full-text
Abstract
Nuclear factor-κB (NF-κB) is a transcription factor regulating a wide array of genes mediating numerous cellular processes such as proliferation, differentiation, motility and survival, to name a few. Aberrant activation of NF-κB is a frequent event in numerous cancers, including glioblastoma, the most
[...] Read more.
Nuclear factor-κB (NF-κB) is a transcription factor regulating a wide array of genes mediating numerous cellular processes such as proliferation, differentiation, motility and survival, to name a few. Aberrant activation of NF-κB is a frequent event in numerous cancers, including glioblastoma, the most common and lethal form of brain tumours of glial cell origin (collectively termed gliomas). Glioblastoma is characterized by high cellular heterogeneity, resistance to therapy and almost inevitable recurrence after surgery and treatment. NF-κB is aberrantly activated in response to a variety of stimuli in glioblastoma, where its activity has been implicated in processes ranging from maintenance of cancer stem-like cells, stimulation of cancer cell invasion, promotion of mesenchymal identity, and resistance to radiotherapy. This review examines the mechanisms of NF-κB activation in glioblastoma, the involvement of NF-κB in several mechanisms underlying glioblastoma propagation, and discusses some of the important questions of future research into the roles of NF-κB in glioblastoma. Full article
Open AccessReview NF-κB in Hematological Malignancies
Biomedicines 2017, 5(2), 27; https://doi.org/10.3390/biomedicines5020027
Received: 28 April 2017 / Revised: 24 May 2017 / Accepted: 26 May 2017 / Published: 31 May 2017
Cited by 2 | PDF Full-text (4385 KB) | HTML Full-text | XML Full-text
Abstract
NF-κB (Nuclear Factor Κ-light-chain-enhancer of activated B cells) transcription factors are critical regulators of immunity, stress response, apoptosis, and differentiation. Molecular defects promoting the constitutive activation of canonical and non-canonical NF-κB signaling pathways contribute to many diseases, including cancer, diabetes, chronic inflammation, and
[...] Read more.
NF-κB (Nuclear Factor Κ-light-chain-enhancer of activated B cells) transcription factors are critical regulators of immunity, stress response, apoptosis, and differentiation. Molecular defects promoting the constitutive activation of canonical and non-canonical NF-κB signaling pathways contribute to many diseases, including cancer, diabetes, chronic inflammation, and autoimmunity. In the present review, we focus our attention on the mechanisms of NF-κB deregulation in hematological malignancies. Key positive regulators of NF-κB signaling can act as oncogenes that are often prone to chromosomal translocation, amplifications, or activating mutations. Negative regulators of NF-κB have tumor suppressor functions, and are frequently inactivated either by genomic deletions or point mutations. NF-κB activation in tumoral cells is also driven by the microenvironment or chronic signaling that does not rely on genetic alterations. Full article
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Open AccessFeature PaperReview NF-κB Members Left Home: NF-κB-Independent Roles in Cancer
Biomedicines 2017, 5(2), 26; https://doi.org/10.3390/biomedicines5020026
Received: 31 March 2017 / Revised: 15 May 2017 / Accepted: 19 May 2017 / Published: 25 May 2017
Cited by 5 | PDF Full-text (6261 KB) | HTML Full-text | XML Full-text
Abstract
Nuclear factor-κB (NF-κB) has been long considered a master regulator of inflammation and immune responses. Additionally, aberrant NF-κB signaling has been linked with carcinogenesis in many types of cancer. In recent years, the study of NF-κB members in NF-κB unrelated pathways provided novel
[...] Read more.
Nuclear factor-κB (NF-κB) has been long considered a master regulator of inflammation and immune responses. Additionally, aberrant NF-κB signaling has been linked with carcinogenesis in many types of cancer. In recent years, the study of NF-κB members in NF-κB unrelated pathways provided novel attractive targets for cancer therapy, specifically linked to particular pathologic responses. Here we review specific functions of IκB kinase complexes (IKKs) and IκBs, which have distinctly tumor promoting or suppressing activities in cancer. Understanding how these proteins are regulated in a tumor-related context will provide new opportunities for drug development. Full article
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Open AccessFeature PaperReview Hypoxia and Inflammation in Cancer, Focus on HIF and NF-κB
Biomedicines 2017, 5(2), 21; https://doi.org/10.3390/biomedicines5020021
Received: 31 March 2017 / Revised: 2 May 2017 / Accepted: 4 May 2017 / Published: 9 May 2017
Cited by 13 | PDF Full-text (2473 KB) | HTML Full-text | XML Full-text
Abstract
Cancer is often characterised by the presence of hypoxia and inflammation. Paramount to the mechanisms controlling cellular responses under such stress stimuli, are the transcription factor families of Hypoxia Inducible Factor (HIF) and Nuclear Factor of κ-light-chain-enhancer of activated B cells (NF-κB). Although,
[...] Read more.
Cancer is often characterised by the presence of hypoxia and inflammation. Paramount to the mechanisms controlling cellular responses under such stress stimuli, are the transcription factor families of Hypoxia Inducible Factor (HIF) and Nuclear Factor of κ-light-chain-enhancer of activated B cells (NF-κB). Although, a detailed understating of how these transcription factors respond to their cognate stimulus is well established, it is now appreciated that HIF and NF-κB undergo extensive crosstalk, in particular in pathological situations such as cancer. Here, we focus on the current knowledge on how HIF is activated by inflammation and how NF-κB is modulated by hypoxia. We summarise the evidence for the possible mechanism behind this activation and how HIF and NF-κB function impacts cancer, focusing on colorectal, breast and lung cancer. We discuss possible new points of therapeutic intervention aiming to harness the current understanding of the HIF-NF-κB crosstalk. Full article
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Open AccessCorrection Correction: Riedlinger, T. et al. The Direct and Indirect Roles of NF-κB in Cancer: Lessons from Oncogenic Fusion Proteins and Knock-In Mice. Biomedicines, 2018, 6, 36
Biomedicines 2018, 6(2), 57; https://doi.org/10.3390/biomedicines6020057
Received: 11 May 2018 / Revised: 14 May 2018 / Accepted: 14 May 2018 / Published: 16 May 2018
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Abstract
We would like to report an error in a previously published paper[...] Full article
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