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Biomedicines
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Roles of NF-κB in Cancer and Their Therapeutic Approaches
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Roles of NF-κB in Cancer and Their Therapeutic Approaches

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular and Translational Medicine".

Deadline for manuscript submissions: closed (1 March 2018) | Viewed by 137959

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

Special Issue Editor

Dr. Veronique Baud

E-Mail Website
Guest Editor
1. NF-kB, Differenciation and Cancer, University Paris Descartes, Sorbonne Paris Cité, 75014 Paris, France
2. Faculté de Pharmacie, 4 Avenue de l'Observatoire, 75006 Paris, France
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 Issues, Collections and Topics in MDPI journals

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

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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 monthly 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 2600 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

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Published Papers (18 papers)

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Research

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9 pages, 2198 KiB  
Article
Deubiquitinylase USP47 Promotes RelA Phosphorylation and Survival in Gastric Cancer Cells
by Lara Naghavi, Martin Schwalbe, Ahmed Ghanem and Michael Naumann
Biomedicines 2018, 6(2), 62; https://doi.org/10.3390/biomedicines6020062 - 22 May 2018
Cited by 16 | Viewed by 4649
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
(This article belongs to the Special Issue Roles of NF-κB in Cancer and Their Therapeutic Approaches)
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Review

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21 pages, 1376 KiB  
Review
Noncanonical NF-κB in Cancer
by Matthew Tegowski and Albert Baldwin
Biomedicines 2018, 6(2), 66; https://doi.org/10.3390/biomedicines6020066 - 05 Jun 2018
Cited by 44 | Viewed by 6200
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
(This article belongs to the Special Issue Roles of NF-κB in Cancer and Their Therapeutic Approaches)
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19 pages, 1059 KiB  
Review
The NF-κB Activating Pathways in Multiple Myeloma
by Payel Roy, Uday Aditya Sarkar and Soumen Basak
Biomedicines 2018, 6(2), 59; https://doi.org/10.3390/biomedicines6020059 - 16 May 2018
Cited by 61 | Viewed by 8223
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
(This article belongs to the Special Issue Roles of NF-κB in Cancer and Their Therapeutic Approaches)
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18 pages, 1928 KiB  
Review
The Crosstalk of Endoplasmic Reticulum (ER) Stress Pathways with NF-κB: Complex Mechanisms Relevant for Cancer, Inflammation and Infection
by M. Lienhard Schmitz, M. Samer Shaban, B. Vincent Albert, Anke Gökçen and Michael Kracht
Biomedicines 2018, 6(2), 58; https://doi.org/10.3390/biomedicines6020058 - 16 May 2018
Cited by 93 | Viewed by 10429
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
(This article belongs to the Special Issue Roles of NF-κB in Cancer and Their Therapeutic Approaches)
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14 pages, 2017 KiB  
Review
NF-κB, the Importance of Being Dynamic: Role and Insights in Cancer
by Federica Colombo, Samuel Zambrano and Alessandra Agresti
Biomedicines 2018, 6(2), 45; https://doi.org/10.3390/biomedicines6020045 - 17 Apr 2018
Cited by 32 | Viewed by 5941
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
(This article belongs to the Special Issue Roles of NF-κB in Cancer and Their Therapeutic Approaches)
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12 pages, 9150 KiB  
Review
Subunit-Specific Role of NF-κB in Cancer
by Barbara Kaltschmidt, Johannes F. W. Greiner, Hussamadin M. Kadhim and Christian Kaltschmidt
Biomedicines 2018, 6(2), 44; https://doi.org/10.3390/biomedicines6020044 - 17 Apr 2018
Cited by 78 | Viewed by 8064
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
(This article belongs to the Special Issue Roles of NF-κB in Cancer and Their Therapeutic Approaches)
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47 pages, 18194 KiB  
Review
The Many Roles of Ubiquitin in NF-κB Signaling
by Gilles Courtois and Marie-Odile Fauvarque
Biomedicines 2018, 6(2), 43; https://doi.org/10.3390/biomedicines6020043 - 10 Apr 2018
Cited by 41 | Viewed by 7528
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
(This article belongs to the Special Issue Roles of NF-κB in Cancer and Their Therapeutic Approaches)
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19 pages, 2399 KiB  
Review
Roles of NF-κB Signaling in the Regulation of miRNAs Impacting on Inflammation in Cancer
by Georgios S. Markopoulos, Eugenia Roupakia, Maria Tokamani, Georgia Alabasi, Raphael Sandaltzopoulos, Kenneth B. Marcu and Evangelos Kolettas
Biomedicines 2018, 6(2), 40; https://doi.org/10.3390/biomedicines6020040 - 30 Mar 2018
Cited by 64 | Viewed by 7180
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
(This article belongs to the Special Issue Roles of NF-κB in Cancer and Their Therapeutic Approaches)
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30 pages, 50756 KiB  
Review
NF-κB Activation in Lymphoid Malignancies: Genetics, Signaling, and Targeted Therapy
by Paula Grondona, Philip Bucher, Klaus Schulze-Osthoff, Stephan Hailfinger and Anja Schmitt
Biomedicines 2018, 6(2), 38; https://doi.org/10.3390/biomedicines6020038 - 26 Mar 2018
Cited by 42 | Viewed by 8304
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
(This article belongs to the Special Issue Roles of NF-κB in Cancer and Their Therapeutic Approaches)
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16 pages, 1742 KiB  
Review
The Direct and Indirect Roles of NF-κB in Cancer: Lessons from Oncogenic Fusion Proteins and Knock-in Mice
by Tabea Riedlinger, Jana Haas, Julia Busch, Bart Van de Sluis, Michael Kracht and M. Lienhard Schmitz
Biomedicines 2018, 6(1), 36; https://doi.org/10.3390/biomedicines6010036 - 19 Mar 2018
Cited by 15 | Viewed by 5191 | 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
(This article belongs to the Special Issue Roles of NF-κB in Cancer and Their Therapeutic Approaches)
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9 pages, 824 KiB  
Review
BET Family Protein BRD4: An Emerging Actor in NFκB Signaling in Inflammation and Cancer
by Azadeh Hajmirza, Anouk Emadali, Arnaud Gauthier, Olivier Casasnovas, Rémy Gressin and Mary B. Callanan
Biomedicines 2018, 6(1), 16; https://doi.org/10.3390/biomedicines6010016 - 06 Feb 2018
Cited by 119 | Viewed by 10798
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
(This article belongs to the Special Issue Roles of NF-κB in Cancer and Their Therapeutic Approaches)
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3919 KiB  
Review
Unlocking the NF-κB Conundrum: Embracing Complexity to Achieve Specificity
by Federica Begalli, Jason Bennett, Daria Capece, Daniela Verzella, Daniel D’Andrea, Laura Tornatore and Guido Franzoso
Biomedicines 2017, 5(3), 50; https://doi.org/10.3390/biomedicines5030050 - 22 Aug 2017
Cited by 50 | Viewed by 8964
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
(This article belongs to the Special Issue Roles of NF-κB in Cancer and Their Therapeutic Approaches)
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1130 KiB  
Review
Aspirin Prevention of Colorectal Cancer: Focus on NF-κB Signalling and the Nucleolus
by Jingyu Chen and Lesley A. Stark
Biomedicines 2017, 5(3), 43; https://doi.org/10.3390/biomedicines5030043 - 18 Jul 2017
Cited by 35 | Viewed by 9804
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
(This article belongs to the Special Issue Roles of NF-κB in Cancer and Their Therapeutic Approaches)
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264 KiB  
Review
NF-κB Signalling in Glioblastoma
by Vincent Soubannier and Stefano Stifani
Biomedicines 2017, 5(2), 29; https://doi.org/10.3390/biomedicines5020029 - 09 Jun 2017
Cited by 83 | Viewed by 5936
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
(This article belongs to the Special Issue Roles of NF-κB in Cancer and Their Therapeutic Approaches)
4385 KiB  
Review
NF-κB in Hematological Malignancies
by Véronique Imbert and Jean-François Peyron
Biomedicines 2017, 5(2), 27; https://doi.org/10.3390/biomedicines5020027 - 31 May 2017
Cited by 37 | Viewed by 5672
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
(This article belongs to the Special Issue Roles of NF-κB in Cancer and Their Therapeutic Approaches)
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6261 KiB  
Review
NF-κB Members Left Home: NF-κB-Independent Roles in Cancer
by Carlota Colomer, Laura Marruecos, Anna Vert, Anna Bigas and Lluis Espinosa
Biomedicines 2017, 5(2), 26; https://doi.org/10.3390/biomedicines5020026 - 25 May 2017
Cited by 38 | Viewed by 5195
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
(This article belongs to the Special Issue Roles of NF-κB in Cancer and Their Therapeutic Approaches)
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Review
Hypoxia and Inflammation in Cancer, Focus on HIF and NF-κB
by Laura D’Ignazio, Michael Batie and Sonia Rocha
Biomedicines 2017, 5(2), 21; https://doi.org/10.3390/biomedicines5020021 - 09 May 2017
Cited by 141 | Viewed by 14519
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
(This article belongs to the Special Issue Roles of NF-κB in Cancer and Their Therapeutic Approaches)
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2 pages, 1291 KiB  
Correction
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
by Tabea Riedlinger, Jana Haas, Julia Busch, Bart Van de Sluis, Michael Kracht and M. Lienhard Schmitz
Biomedicines 2018, 6(2), 57; https://doi.org/10.3390/biomedicines6020057 - 16 May 2018
Cited by 4 | Viewed by 3205
Abstract
We would like to report an error in a previously published paper[...] Full article
(This article belongs to the Special Issue Roles of NF-κB in Cancer and Their Therapeutic Approaches)
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