Research

11 pages, 1413 KiB

Open AccessArticle

The Alternative RelB NF-kB Subunit Exerts a Critical Survival Function upon Metabolic Stress in Diffuse Large B-Cell Lymphoma-Derived Cells

by Stéphanie Nuan-Aliman, Didier Bordereaux, Catherine Thieblemont and Véronique Baud

Biomedicines 2022, 10(2), 348; https://doi.org/10.3390/biomedicines10020348 - 01 Feb 2022

Cited by 5 | Viewed by 2179

Abstract

Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma in adults and reveals distinct genetic and metabolic signatures. NF-κB transcription factor family is involved in diverse biological processes enabling tumor development and resistance to anticancer-therapy through activation of its two main [...] Read more.

Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma in adults and reveals distinct genetic and metabolic signatures. NF-κB transcription factor family is involved in diverse biological processes enabling tumor development and resistance to anticancer-therapy through activation of its two main pathways, the canonical and the alternative NF-κB pathways, the main actor of the latter being the RelB NF-kB subunit. RelB DNA binding activity is frequently activated in DLBCL patients and cell lines. RelB activation defines a new DLBCL subgroup with dismal outcome upon immunochemotherapy, and RelB confers DLBCL cell resistance to DNA damage. However, whether RelB can impact on DLBCL cell metabolism and survival upon metabolic stress is unknown. Here, we reveal that RelB controls DLBCL oxidative energetic metabolism. Accordingly, RelB inhibition reduce DLBCL mitochondrial ATP production, and sensitizes DLBCL cells to apoptosis induced by Metformin and L-asparaginase (^®Kidrolase), two FDA approved antimetabolic drugs targeting mitochondrial metabolism. RelB also confers DLBCL cell resistance to glutamine deprivation, an essential amino acid that feeds the TCA cycle. Taken together, our findings uncover a new role for RelB in the regulation of DLBCL cell metabolism and DLBCL cell survival upon metabolic stress. Full article

(This article belongs to the Special Issue Roles of NF-κB in Cancer and Their Therapeutic Approaches 2.0)

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22 pages, 3817 KiB

Open AccessArticle

Patient-Specific Modeling of Diffuse Large B-Cell Lymphoma

by Kirsten Thobe, Fabian Konrath, Björn Chapuy and Jana Wolf

Biomedicines 2021, 9(11), 1655; https://doi.org/10.3390/biomedicines9111655 - 10 Nov 2021

Cited by 2 | Viewed by 2287

Abstract

Personalized medicine aims to tailor treatment to patients based on their individual genetic or molecular background. Especially in diseases with a large molecular heterogeneity, such as diffuse large B-cell lymphoma (DLBCL), personalized medicine has the potential to improve outcome and/or to reduce resistance [...] Read more.

Personalized medicine aims to tailor treatment to patients based on their individual genetic or molecular background. Especially in diseases with a large molecular heterogeneity, such as diffuse large B-cell lymphoma (DLBCL), personalized medicine has the potential to improve outcome and/or to reduce resistance towards treatment. However, integration of patient-specific information into a computational model is challenging and has not been achieved for DLBCL. Here, we developed a computational model describing signaling pathways and expression of critical germinal center markers. The model integrates the regulatory mechanism of the signaling and gene expression network and covers more than 50 components, many carrying genetic lesions common in DLBCL. Using clinical and genomic data of 164 primary DLBCL patients, we implemented mutations, structural variants and copy number alterations as perturbations in the model using the CoLoMoTo notebook. Leveraging patient-specific genotypes and simulation of the expression of marker genes in specific germinal center conditions allows us to predict the consequence of the modeled pathways for each patient. Finally, besides modeling how genetic perturbations alter physiological signaling, we also predicted for each patient model the effect of rational inhibitors, such as Ibrutinib, that are currently discussed as possible DLBCL treatments, showing patient-dependent variations in effectiveness and synergies. Full article

(This article belongs to the Special Issue Roles of NF-κB in Cancer and Their Therapeutic Approaches 2.0)

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9 pages, 2198 KiB

Open AccessArticle

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 4671

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

Jump to: Research, Other

17 pages, 1882 KiB

Open AccessReview

Repeat Element Activation-Driven Inflammation: Role of NFκB and Implications in Normal Development and Cancer?

by Baptiste Dumetier, Camille Sauter, Azadeh Hajmirza, Baptiste Pernon, Romain Aucagne, Cyril Fournier, Céline Row, Fabien Guidez, Cédric Rossi, Côme Lepage, Laurent Delva and Mary B. Callanan

Biomedicines 2022, 10(12), 3101; https://doi.org/10.3390/biomedicines10123101 - 01 Dec 2022

Cited by 3 | Viewed by 1896

Abstract

The human genome is composed of unique DNA sequences that encode proteins and unique sequence noncoding RNAs that are essential for normal development and cellular differentiation. The human genome also contains over 50% of genome sequences that are repeat in nature (tandem and [...] Read more.

The human genome is composed of unique DNA sequences that encode proteins and unique sequence noncoding RNAs that are essential for normal development and cellular differentiation. The human genome also contains over 50% of genome sequences that are repeat in nature (tandem and interspersed repeats) that are now known to contribute dynamically to genetic diversity in populations, to be transcriptionally active under certain physiological conditions, and to be aberrantly active in disease states including cancer, where consequences are pleiotropic with impact on cancer cell phenotypes and on the tumor immune microenvironment. Repeat element-derived RNAs play unique roles in exogenous and endogenous cell signaling under normal and disease conditions. A key component of repeat element-derived transcript-dependent signaling occurs via triggering of innate immune receptor signaling that then feeds forward to inflammatory responses through interferon and NFκB signaling. It has recently been shown that cancer cells display abnormal transcriptional activity of repeat elements and that this is linked to either aggressive disease and treatment failure or to improved prognosis/treatment response, depending on cell context and the amplitude of the so-called ‘viral mimicry’ response that is engaged. ‘Viral mimicry’ refers to a cellular state of active antiviral response triggered by endogenous nucleic acids often derived from aberrantly transcribed endogenous retrotransposons and other repeat elements. In this paper, the literature regarding transcriptional activation of repeat elements and engagement of inflammatory signaling in normal (focusing on hematopoiesis) and cancer is reviewed with an emphasis on the role of innate immune receptor signaling, in particular by dsRNA receptors of the RIG-1 like receptor family and interferons/NFκB. How repeat element-derived RNA reprograms cell identity through RNA-guided chromatin state modulation is also discussed. Full article

(This article belongs to the Special Issue Roles of NF-κB in Cancer and Their Therapeutic Approaches 2.0)

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23 pages, 1825 KiB

Open AccessReview

NF-κB Mutations in Germinal Center B-Cell Lymphomas: Relation to NF-κB Function in Normal B Cells

by Laura Pasqualucci and Ulf Klein

Biomedicines 2022, 10(10), 2450; https://doi.org/10.3390/biomedicines10102450 - 01 Oct 2022

Cited by 8 | Viewed by 3824

Abstract

Most B cell lymphomas arise from the oncogenic transformation of B cells that have undergone the germinal center (GC) reaction of the T cell-dependent immune response, where high-affinity memory B cells and plasma cells are generated. The high proliferation of GC B cells [...] Read more.

Most B cell lymphomas arise from the oncogenic transformation of B cells that have undergone the germinal center (GC) reaction of the T cell-dependent immune response, where high-affinity memory B cells and plasma cells are generated. The high proliferation of GC B cells coupled with occasional errors in the DNA-modifying processes of somatic hypermutation and class switch recombination put the cell at a risk to obtain transforming genetic aberrations, which may activate proto-oncogenes or inactivate tumour suppressor genes. Several subtypes of GC lymphomas harbor genetic mutations leading to constitutive, aberrant activation of the nuclear factor-κB (NF-κB) signaling pathway. In normal B cells, NF-κB has crucial biological roles in development and physiology. GC lymphomas highjack these activities to promote tumour-cell growth and survival. It has become increasingly clear that the separate canonical and non-canonical routes of the NF-κB pathway and the five downstream NF-κB transcription factors have distinct functions in the successive stages of GC B-cell development. These findings may have direct implications for understanding how aberrant NF-κB activation promotes the genesis of various GC lymphomas corresponding to the developmentally distinct GC B-cell subsets. The knowledge arising from these studies may be explored for the development of precision medicine approaches aimed at more effective treatments of the corresponding tumours with specific NF-κB inhibitors, thus reducing systemic toxicity. We here provide an overview on the patterns of genetic NF-κB mutations encountered in the various GC lymphomas and discuss the consequences of aberrant NF-κB activation in those malignancies as related to the biology of NF-κB in their putative normal cellular counterparts. Full article

(This article belongs to the Special Issue Roles of NF-κB in Cancer and Their Therapeutic Approaches 2.0)

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18 pages, 1247 KiB

Open AccessReview

Dynamic Regulation of NF-κB Response in Innate Immunity: The Case of the IMD Pathway in Drosophila

by Alexandre Cammarata-Mouchtouris, Adrian Acker, Akira Goto, Di Chen, Nicolas Matt and Vincent Leclerc

Biomedicines 2022, 10(9), 2304; https://doi.org/10.3390/biomedicines10092304 - 16 Sep 2022

Cited by 12 | Viewed by 3741

Abstract

Metazoans have developed strategies to protect themselves from pathogenic attack. These preserved mechanisms constitute the immune system, composed of innate and adaptive responses. Among the two kinds, the innate immune system involves the activation of a fast response. NF-κB signaling pathways are activated [...] Read more.

Metazoans have developed strategies to protect themselves from pathogenic attack. These preserved mechanisms constitute the immune system, composed of innate and adaptive responses. Among the two kinds, the innate immune system involves the activation of a fast response. NF-κB signaling pathways are activated during infections and lead to the expression of timely-controlled immune response genes. However, activation of NF-κB pathways can be deleterious when uncontrolled. Their regulation is necessary to prevent the development of inflammatory diseases or cancers. The similarity of the NF-κB pathways mediating immune mechanisms in insects and mammals makes Drosophila melanogaster a suitable model for studying the innate immune response and learning general mechanisms that are also relevant for humans. In this review, we summarize what is known about the dynamic regulation of the central NF-κB-pathways and go into detail on the molecular level of the IMD pathway. We report on the role of the nuclear protein Akirin in the regulation of the NF-κB Relish immune response. The use of the Drosophila model allows the understanding of the fine-tuned regulation of this central NF-κB pathway. Full article

(This article belongs to the Special Issue Roles of NF-κB in Cancer and Their Therapeutic Approaches 2.0)

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37 pages, 2260 KiB

Open AccessReview

The NF-κB Pharmacopeia: Novel Strategies to Subdue an Intractable Target

by Daniela Verzella, Jessica Cornice, Paola Arboretto, Davide Vecchiotti, Mauro Di Vito Nolfi, Daria Capece, Francesca Zazzeroni and Guido Franzoso

Biomedicines 2022, 10(9), 2233; https://doi.org/10.3390/biomedicines10092233 - 08 Sep 2022

Cited by 7 | Viewed by 3623

Abstract

NF-κB transcription factors are major drivers of tumor initiation and progression. NF-κB signaling is constitutively activated by genetic alterations or environmental signals in many human cancers, where it contributes to almost all hallmarks of malignancy, including sustained proliferation, cell death resistance, tumor-promoting inflammation, [...] Read more.

NF-κB transcription factors are major drivers of tumor initiation and progression. NF-κB signaling is constitutively activated by genetic alterations or environmental signals in many human cancers, where it contributes to almost all hallmarks of malignancy, including sustained proliferation, cell death resistance, tumor-promoting inflammation, metabolic reprogramming, tissue invasion, angiogenesis, and metastasis. As such, the NF-κB pathway is an attractive therapeutic target in a broad range of human cancers, as well as in numerous non-malignant diseases. Currently, however, there is no clinically useful NF-κB inhibitor to treat oncological patients, owing to the preclusive, on-target toxicities of systemic NF-κB blockade. In this review, we discuss the principal and most promising strategies being developed to circumvent the inherent limitations of conventional IκB kinase (IKK)/NF-κB-targeting drugs, focusing on new molecules that target upstream regulators or downstream effectors of oncogenic NF-κB signaling, as well as agents targeting individual NF-κB subunits. Full article

(This article belongs to the Special Issue Roles of NF-κB in Cancer and Their Therapeutic Approaches 2.0)

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12 pages, 807 KiB

Open AccessReview

NFkB Pathway and Hodgkin Lymphoma

by Fabrice Jardin

Biomedicines 2022, 10(9), 2153; https://doi.org/10.3390/biomedicines10092153 - 01 Sep 2022

Cited by 4 | Viewed by 3489

Abstract

The tumor cells that drive classical Hodgkin lymphoma (cHL), namely, Hodgkin and Reed-Sternberg (HRS) cells, display hallmark features that include their rareness in contrast with an extensive and rich reactive microenvironment, their loss of B-cell phenotype markers, their immune escape capacity, and the [...] Read more.

The tumor cells that drive classical Hodgkin lymphoma (cHL), namely, Hodgkin and Reed-Sternberg (HRS) cells, display hallmark features that include their rareness in contrast with an extensive and rich reactive microenvironment, their loss of B-cell phenotype markers, their immune escape capacity, and the activation of several key biological pathways, including the constitutive activation of the NFkB pathway. Both canonical and alternative pathways are deregulated by genetic alterations of their components or regulators, EBV infection and interaction with the microenvironment through multiple receptors, including CD30, CD40, BAFF, RANK and BCMA. Therefore, NFkB target genes are involved in apoptosis, cell proliferation, JAK/STAT pathway activation, B-cell marker expression loss, cellular interaction and a positive NFkB feedback loop. Targeting this complex pathway directly (NIK inhibitors) or indirectly (PIM, BTK or NOTCH) remains a challenge with potential therapeutic relevance. Nodular predominant HL (NLPHL), a distinct and rare HL subtype, shows a strong NFkB activity signature because of mechanisms that differ from those observed in cHL, which is discussed in this review. Full article

(This article belongs to the Special Issue Roles of NF-κB in Cancer and Their Therapeutic Approaches 2.0)

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16 pages, 1481 KiB

Open AccessReview

Post-Transcriptional Control of mRNA Metabolism and Protein Secretion: The Third Level of Regulation within the NF-κB System

by Jasmin Priester, Jan Dreute, Michael Kracht and M. Lienhard Schmitz

Biomedicines 2022, 10(9), 2108; https://doi.org/10.3390/biomedicines10092108 - 29 Aug 2022

Cited by 3 | Viewed by 1833

Abstract

The NF-κB system is a key transcriptional pathway that regulates innate and adaptive immunity because it triggers the activation and differentiation processes of lymphocytes and myeloid cells during immune responses. In most instances, binding to cytoplasmic inhibitory IκB proteins sequesters NF-κB into an [...] Read more.

The NF-κB system is a key transcriptional pathway that regulates innate and adaptive immunity because it triggers the activation and differentiation processes of lymphocytes and myeloid cells during immune responses. In most instances, binding to cytoplasmic inhibitory IκB proteins sequesters NF-κB into an inactive state, while a plethora of external triggers activate three complex signaling cascades that mediate the release and nuclear translocation of the NF-κB DNA-binding subunits. In addition to these cytosolic steps (level 1 of NF-κB regulation), NF-κB activity is also controlled in the nucleus by signaling events, cofactors and the chromatin environment to precisely determine chromatin recruitment and the specificity and timing of target gene transcription (level 2 of NF-κB regulation). Here, we discuss an additional layer of the NF-κB system that manifests in various steps of post-transcriptional gene expression and protein secretion. This less-studied regulatory level allows reduction of (transcriptional) noise and signal integration and endows time-shifted control of the secretion of inflammatory mediators. Detailed knowledge of these steps is important, as dysregulated post-transcriptional NF-κB signaling circuits are likely to foster chronic inflammation and contribute to the formation and maintenance of a tumor-promoting microenvironment. Full article

(This article belongs to the Special Issue Roles of NF-κB in Cancer and Their Therapeutic Approaches 2.0)

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13 pages, 1099 KiB

Open AccessReview

NF-κB: A Double-Edged Sword Controlling Inflammation

by Danhui Liu, Zhenyu Zhong and Michael Karin

Biomedicines 2022, 10(6), 1250; https://doi.org/10.3390/biomedicines10061250 - 27 May 2022

Cited by 34 | Viewed by 4188

Abstract

Inflammation, when properly mounted and precisely calibrated, is a beneficial process that enables the rapid removal of invading pathogens and/or cellular corpses and promotes tissue repair/regeneration to restore homeostasis after injury. Being a paradigm of a rapid response transcription factor, the nuclear factor-kappa [...] Read more.

Inflammation, when properly mounted and precisely calibrated, is a beneficial process that enables the rapid removal of invading pathogens and/or cellular corpses and promotes tissue repair/regeneration to restore homeostasis after injury. Being a paradigm of a rapid response transcription factor, the nuclear factor-kappa B (NF-κB) transcription factor family plays a central role in amplifying inflammation by inducing the expression of inflammatory cytokines and chemokines. Additionally, NF-κB also induces the expression of pro-survival and -proliferative genes responsible for promoting tissue repair and regeneration. Paradoxically, recent studies have suggested that the NF-κB pathway can also exert inhibitory effects on pro-inflammatory cytokine production to temper inflammation. Here, we review our current understanding about the pro- and anti-inflammatory roles of NF-κB and discuss the implication of its dichotomous inflammation-modulating activity in the context of inflammasome activation and tumorigenesis. Full article

(This article belongs to the Special Issue Roles of NF-κB in Cancer and Their Therapeutic Approaches 2.0)

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15 pages, 1291 KiB

Open AccessReview

Controlling Cancer Cell Death Types to Optimize Anti-Tumor Immunity

by Marie Oliver Metzig and Alexander Hoffmann

Biomedicines 2022, 10(5), 974; https://doi.org/10.3390/biomedicines10050974 - 22 Apr 2022

Viewed by 1919

Abstract

Over several decades, cell biology research has characterized distinct forms of regulated cell death, identified master regulators such as nuclear factor kappa B (NFκB), and contributed to translating these findings in order to improve anti-cancer therapies. In the era of immunotherapy, however, the [...] Read more.

Over several decades, cell biology research has characterized distinct forms of regulated cell death, identified master regulators such as nuclear factor kappa B (NFκB), and contributed to translating these findings in order to improve anti-cancer therapies. In the era of immunotherapy, however, the field warrants a new appraisal—the targeted induction of immunogenic cell death may offer personalized strategies to optimize anti-tumor immunity. Once again, the spotlight is on NFκB, which is not only a master regulator of cancer cell death, survival, and inflammation, but also of adaptive anti-tumor immune responses that are triggered by dying tumor cells. Full article

(This article belongs to the Special Issue Roles of NF-κB in Cancer and Their Therapeutic Approaches 2.0)

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15 pages, 1237 KiB

Open AccessReview

The Paracaspase MALT1 in Cancer

by Beatriz Gomez Solsona, Anja Schmitt, Klaus Schulze-Osthoff and Stephan Hailfinger

Biomedicines 2022, 10(2), 344; https://doi.org/10.3390/biomedicines10020344 - 01 Feb 2022

Cited by 13 | Viewed by 3590

Abstract

Almost twenty years ago, the importance of the paracaspase MALT1 in antigen receptor-induced NF-κB activation was first described. Since then, several other immune receptors, G-protein-coupled receptors, and receptor tyrosine kinases were identified as relying on MALT1 to induce NF-κB activation. In various hematological [...] Read more.

Almost twenty years ago, the importance of the paracaspase MALT1 in antigen receptor-induced NF-κB activation was first described. Since then, several other immune receptors, G-protein-coupled receptors, and receptor tyrosine kinases were identified as relying on MALT1 to induce NF-κB activation. In various hematological malignancies and solid tumors, MALT1 is constitutively activated and drives chronic NF-κB target gene expression. Deregulated MALT1 activity in cancer thus promotes tumor cell survival, proliferation, and metastasis. Since the molecular function of MALT1 partially requires its protease activity, pharmacological targeting of MALT1 may represent a promising anti-cancer strategy. Here, we review the molecular features of MALT1 activation and function as well as the therapeutic potential of MALT1 inhibition in hematological malignancies and solid tumors. Full article

(This article belongs to the Special Issue Roles of NF-κB in Cancer and Their Therapeutic Approaches 2.0)

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15 pages, 10537 KiB

Open AccessReview

Targeting NF-κB Signaling in Cancer Stem Cells: A Narrative Review

by Barbara Kaltschmidt, Kaya E. Witte, Johannes F. W. Greiner, Florian Weissinger and Christian Kaltschmidt

Biomedicines 2022, 10(2), 261; https://doi.org/10.3390/biomedicines10020261 - 25 Jan 2022

Cited by 13 | Viewed by 3422

Abstract

Among the cell populations existing within a tumor, cancer stem cells are responsible for metastasis formation and chemotherapeutic resistance. In the present review, we focus on the transcription factor NF-κB, which is present in every cell type including cancer stem cells. NF-κB is [...] Read more.

Among the cell populations existing within a tumor, cancer stem cells are responsible for metastasis formation and chemotherapeutic resistance. In the present review, we focus on the transcription factor NF-κB, which is present in every cell type including cancer stem cells. NF-κB is involved in pro-tumor inflammation by its target gene interleukin 1 (IL1) and can be activated by a feed-forward loop in an IL1-dependent manner. Here, we summarize current strategies targeting NF-κB by chemicals and biologicals within an integrated cancer therapy. Specifically, we start with a tyrosine kinase inhibitor targeting epidermal growth factor (EGF)-receptor-mediated phosphorylation. Furthermore, we summarize current strategies of multiple myeloma treatment involving lenalidomide, bortezomib, and dexamethasone as potential NF-κB inhibitors. Finally, we discuss programmed death-ligand 1 (PD-L1) as an NF-κB target gene and its role in checkpoint therapy. We conclude, that NF-κB inhibition by specific inhibitors of IκB kinase was of no clinical use but inhibition of upstream and downstream targets with drugs or biologicals might be a fruitful way to treat cancer stem cells. Full article

(This article belongs to the Special Issue Roles of NF-κB in Cancer and Their Therapeutic Approaches 2.0)

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11 pages, 1127 KiB

Open AccessReview

NF-κB-Dependent and -Independent (Moonlighting) IκBα Functions in Differentiation and Cancer

by Lluís Espinosa and Laura Marruecos

Biomedicines 2021, 9(9), 1278; https://doi.org/10.3390/biomedicines9091278 - 21 Sep 2021

Cited by 4 | Viewed by 2322

Abstract

IκBα is considered to play an almost exclusive role as inhibitor of the NF-κB signaling pathway. However, previous results have demonstrated that SUMOylation imposes a distinct subcellular distribution, regulation, NF-κB-binding affinity and function to the IκBα protein. In this review we discuss the [...] Read more.

IκBα is considered to play an almost exclusive role as inhibitor of the NF-κB signaling pathway. However, previous results have demonstrated that SUMOylation imposes a distinct subcellular distribution, regulation, NF-κB-binding affinity and function to the IκBα protein. In this review we discuss the main alterations of IκBα found in cancer and whether they are (most likely) associated with NF-κB-dependent or NF-κB-independent (moonlighting) activities of the protein. Full article

(This article belongs to the Special Issue Roles of NF-κB in Cancer and Their Therapeutic Approaches 2.0)

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16 pages, 1869 KiB

Open AccessReview

The NF-κB Nucleolar Stress Response Pathway

by Hazel C. Thoms and Lesley A. Stark

Biomedicines 2021, 9(9), 1082; https://doi.org/10.3390/biomedicines9091082 - 25 Aug 2021

Cited by 12 | Viewed by 3602

Abstract

The nuclear organelle, the nucleolus, plays a critical role in stress response and the regulation of cellular homeostasis. P53 as a downstream effector of nucleolar stress is well defined. However, new data suggests that NF-κB also acts downstream of nucleolar stress to regulate [...] Read more.

The nuclear organelle, the nucleolus, plays a critical role in stress response and the regulation of cellular homeostasis. P53 as a downstream effector of nucleolar stress is well defined. However, new data suggests that NF-κB also acts downstream of nucleolar stress to regulate cell growth and death. In this review, we will provide insight into the NF-κB nucleolar stress response pathway. We will discuss apoptosis mediated by nucleolar sequestration of RelA and new data demonstrating a role for p62 (sequestosome (SQSTM1)) in this process. We will also discuss activation of NF-κB signalling by degradation of the RNA polymerase I (PolI) complex component, transcription initiation factor-IA (TIF-IA (RRN3)), and contexts where TIF-IA-NF-κB signalling may be important. Finally, we will discuss how this pathway is targeted by aspirin to mediate apoptosis of colon cancer cells. Full article

(This article belongs to the Special Issue Roles of NF-κB in Cancer and Their Therapeutic Approaches 2.0)

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14 pages, 692 KiB

Open AccessReview

NF-κB and Human Cancer: What Have We Learned over the Past 35 Years?

by Thomas D. Gilmore

Biomedicines 2021, 9(8), 889; https://doi.org/10.3390/biomedicines9080889 - 25 Jul 2021

Cited by 21 | Viewed by 3033

Abstract

Transcription factor NF-κB has been extensively studied for its varied roles in cancer development since its initial characterization as a potent retroviral oncogene. It is now clear that NF-κB also plays a major role in a large variety of human cancers, including especially [...] Read more.

Transcription factor NF-κB has been extensively studied for its varied roles in cancer development since its initial characterization as a potent retroviral oncogene. It is now clear that NF-κB also plays a major role in a large variety of human cancers, including especially ones of immune cell origin. NF-κB is generally constitutively or aberrantly activated in human cancers where it is involved. These activations can occur due to mutations in the NF-κB transcription factors themselves, in upstream regulators of NF-κB, or in pathways that impact NF-κB. In addition, NF-κB can be activated by tumor-assisting processes such as inflammation, stromal effects, and genetic or epigenetic changes in chromatin. Aberrant NF-κB activity can affect many tumor-associated processes, including cell survival, cell cycle progression, inflammation, metastasis, angiogenesis, and regulatory T cell function. As such, inhibition of NF-κB has often been investigated as an anticancer strategy. Nevertheless, with a few exceptions, NF-κB inhibition has had limited success in human cancer treatment. This review covers general themes that have emerged regarding the biological roles and mechanisms by which NF-κB contributes to human cancers and new thoughts on how NF-κB may be targeted for cancer prognosis or therapy. Full article

(This article belongs to the Special Issue Roles of NF-κB in Cancer and Their Therapeutic Approaches 2.0)

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21 pages, 660 KiB

Open AccessReview

NF-κB in Gastric Cancer Development and Therapy

by Supattra Chaithongyot, Phatcharida Jantaree, Olga Sokolova and Michael Naumann

Biomedicines 2021, 9(8), 870; https://doi.org/10.3390/biomedicines9080870 - 23 Jul 2021

Cited by 20 | Viewed by 3180

Abstract

Gastric cancer is considered one of the most common causes of cancer-related death worldwide and, thus, a major health problem. A variety of environmental factors including physical and chemical noxae, as well as pathogen infections could contribute to the development of gastric cancer. [...] Read more.

Gastric cancer is considered one of the most common causes of cancer-related death worldwide and, thus, a major health problem. A variety of environmental factors including physical and chemical noxae, as well as pathogen infections could contribute to the development of gastric cancer. The transcription factor nuclear factor kappa B (NF-κB) and its dysregulation has a major impact on gastric carcinogenesis due to the regulation of cytokines/chemokines, growth factors, anti-apoptotic factors, cell cycle regulators, and metalloproteinases. Changes in NF-κB signaling are directed by genetic alterations in the transcription factors themselves, but also in NF-κB signaling molecules. NF-κB actively participates in the crosstalk of the cells in the tumor micromilieu with divergent effects on the heterogeneous tumor cell and immune cell populations. Thus, the benefits/consequences of therapeutic targeting of NF-κB have to be carefully evaluated. In this review, we address recent knowledge about the mechanisms and consequences of NF-κB dysregulation in gastric cancer development and therapy. Full article

(This article belongs to the Special Issue Roles of NF-κB in Cancer and Their Therapeutic Approaches 2.0)

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21 pages, 1376 KiB

Open AccessReview

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 6219

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

Open AccessReview

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 8243

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

Open AccessReview

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 10466

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

Open AccessReview

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 5968

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

Open AccessReview

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 8095

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

Open AccessReview

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 7552

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

Open AccessReview

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 7202

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

Open AccessFeature PaperReview

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 8510

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

Open AccessReview

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 5206 | 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

Open AccessReview

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 10871

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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Open AccessReview

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 8998

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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Open AccessReview

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 9827

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

Open AccessFeature PaperReview

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 5948

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)

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Open AccessReview

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 5696

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

Open AccessFeature PaperReview

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 5219

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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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 14737

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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3 pages, 448 KiB

Open AccessObituary

Obituary for Prof. Dr. Ulrich Siebenlist

by Philip M. Murphy and Michael J. Lenardo

Biomedicines 2021, 9(3), 244; https://doi.org/10.3390/biomedicines9030244 - 01 Mar 2021

Viewed by 1289

Abstract

Ulrich Siebenlist, Ph [...] Full article

(This article belongs to the Special Issue Roles of NF-κB in Cancer and Their Therapeutic Approaches 2.0)

2 pages, 1291 KiB

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

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 3216

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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