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Cancers
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NF-kB Signaling in Cellular Responses to Threats, Cancer Development and...
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NF-kB Signaling in Cellular Responses to Threats, Cancer Development and Therapy

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 24673

Special Issue Editors

Dr. Evangelos Kolettas

E-Mail Website
Guest Editor
1. Laboratory of Biology, School of Medicine, Faculty of Health Sciences, and Institute of Biosciences, University Research Centre, University of Ioannina, 451 10 Ioannina, Greece
2. Molecular Cancer Biology & Senescence Labortaory, Biomedical Research Institute (BRI), Foundation for Research and Technology (FORTH), Ioannina, Greece
Interests: cancer; senescence; DNA damage; inflammation; epithelial-to-mesenchymal cell transition; cell signalling; NF-kappaB; transcriptional regulation; epigenetics; miRNA
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Kenneth B. Marcu

E-Mail Website1 Website2
Guest Editor
Biochemistry and Cell Biology Department, Stony Brook University, Life Sciences Rm#330, Stony Brook, NY 11794-5215, USA
Interests: gene expression control; mechanisms of cancer development; IKKalpha and IKKbeta NFkappaB activating kinases
Special Issues, Collections and Topics in MDPI journals
Dr. Johannes A. Schmid

E-Mail Website
Guest Editor
Department of Vascular Biology and Thrombosis Research, Center for Physiology and Pharmacology, Medical University of Vienna, Schwarzspanierstr. 17, A1090 Vienna, Austria
Interests: inflammation; cancer; thrombosis; microscopy; omics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear colleagues,

NF-kappaB (NF-kB) transcription factors are involved in a multitude of responses to stress or danger signals and regulate inflammation as well as cellular development, cell growth, and survival. Selectivity and redundancy in NF-kB mediated transcription involves the assembly of homodimers and heterodimers of five different NF-kB proteins (RelA/p65, RelB, c-Rel, NF-kB1/p105 and NF-kB2/p100) which are tethered in the cytoplasm by inhibitory proteins (IkBa, IkBb, IkBe, IkBg/p100). Activation of NF-kBs involves an IκB-kinase complex consisting of two serine–threonine kinases, IKKa (IKK1) and IKKb (IKK2), and a regulatory or docking protein, IKKg (NEMO), that facilitates IKK complex assembly and transmits upstream activating signals to IKKa and IKKb. NF-kB signaling is activated by two main pathways: an IKKb-mediated canonical NF-kB pathway involving the nuclear translocation of c-Rel/p50 and RelA(p65)/p50 heterodimers in response to a pro-inflammatory/stress-like signal; and an IKKa-mediated noncanonical or alternative NF-kB pathway in which IKKa is activated by NF-kB inducing kinase (NIK) to generate mature p52-RelB heterodimers which undergo nuclear translocation and influence gene expression. IKKa and IKKb kinases have both NF-kB-dependent and -independent roles, and are involved in the regulation of many cellular processes under normal, stress, and disease conditions.

The purpose of this joint Cancers-Cells Special Issue is to focus on cutting edge research in the field of NF-kB signaling in both health and disease, and to elucidate links with other signaling pathways regulating complex cellular and molecular processes, including cell growth, metabolic reprogramming, and epigenetics. This Special Issue also focuses on the roles of aberrant NF-kB signaling in cardiovascular disease, inflammation-related diseases, and cancer as well as anticancer strategies targeting NF-kB. We invite authors to submit original research and novel review articles on either basic or translational research on this specific topic.

Dr. Evangelos Kolettas
Prof. Emeritus Kenneth B. Marcu
Prof. Johannes A. Schmid
Guest Editors

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. Cancers is an international peer-reviewed open access semimonthly 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 2900 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-kB subunits
  • IkB kinases
  • Signaling networks
  • Feedback circuits
  • Inflammation
  • Immune defense
  • Apoptosis and cell survival
  • Danger-associated molecular patterns (DAMPs)
  • Pathogen-associated molecular patterns (PAMPs)
  • In vitro and mouse models
  • Malignancies
  • Anticancer approaches
  • Links between inflammation, cancer, and cardiovascular diseases
  • Cancer cell metabolism

Related Special Issue

Published Papers (7 papers)

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Research

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23 pages, 8451 KiB  
Article
Antagonistic Functions of Androgen Receptor and NF-κB in Prostate Cancer—Experimental and Computational Analyses
by José Basílio, Bernhard Hochreiter, Bastian Hoesel, Emira Sheshori, Marion Mussbacher, Rudolf Hanel and Johannes A. Schmid
Cancers 2022, 14(24), 6164; https://doi.org/10.3390/cancers14246164 - 14 Dec 2022
Cited by 4 | Viewed by 2787
Abstract
Prostate cancer is very frequent and is, in many countries, the third-leading cause of cancer related death in men. While early diagnosis and treatment by surgical removal is often curative, metastasizing prostate cancer has a very bad prognosis. Based on the androgen-dependence of [...] Read more.
Prostate cancer is very frequent and is, in many countries, the third-leading cause of cancer related death in men. While early diagnosis and treatment by surgical removal is often curative, metastasizing prostate cancer has a very bad prognosis. Based on the androgen-dependence of prostate epithelial cells, the standard treatment is blockade of the androgen receptor (AR). However, nearly all patients suffer from a tumor relapse as the metastasizing cells become AR-independent. In our study we show a counter-regulatory link between AR and NF-κB both in human cells and in mouse models of prostate cancer, implying that inhibition of AR signaling results in induction of NF-κB-dependent inflammatory pathways, which may even foster the survival of metastasizing cells. This could be shown by reporter gene assays, DNA-binding measurements, and immune-fluorescence microscopy, and furthermore by a whole set of computational methods using a variety of datasets. Interestingly, loss of PTEN, a frequent genetic alteration in prostate cancer, also causes an upregulation of NF-κB and inflammatory activity. Finally, we present a mathematical model of a dynamic network between AR, NF-κB/IκB, PI3K/PTEN, and the oncogene c-Myc, which indicates that AR blockade may upregulate c-Myc together with NF-κB, and that combined anti-AR/anti-NF-κB and anti-PI3K treatment might be beneficial. Full article
(This article belongs to the Special Issue NF-kB Signaling in Cellular Responses to Threats, Cancer Development and Therapy)
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16 pages, 3022 KiB  
Article
An Expanded Interplay Network between NF-κB p65 (RelA) and E2F1 Transcription Factors: Roles in Physiology and Pathology
by Spyros Foutadakis, Eugenia Roupakia, Panagiotis Liakopoulos, Petros Kolovos and Evangelos Kolettas
Cancers 2022, 14(20), 5047; https://doi.org/10.3390/cancers14205047 - 14 Oct 2022
Cited by 1 | Viewed by 1954
Abstract
Transcription Factors (TFs) are the main regulators of gene expression, controlling among others cell homeostasis, identity, and fate. TFs may either act synergistically or antagonistically on nearby regulatory elements and their interplay may activate or repress gene expression. The family of NF-κB TFs [...] Read more.
Transcription Factors (TFs) are the main regulators of gene expression, controlling among others cell homeostasis, identity, and fate. TFs may either act synergistically or antagonistically on nearby regulatory elements and their interplay may activate or repress gene expression. The family of NF-κB TFs is among the most important TFs in the regulation of inflammation, immunity, and stress-like responses, while they also control cell growth and survival, and are involved in inflammatory diseases and cancer. The family of E2F TFs are major regulators of cell cycle progression in most cell types. Several studies have suggested the interplay between these two TFs in the regulation of numerous genes controlling several biological processes. In the present study, we compared the genomic binding landscape of NF-κB RelA/p65 subunit and E2F1 TFs, based on high throughput ChIP-seq and RNA-seq data in different cell types. We confirmed that RelA/p65 has a binding profile with a high preference for distal enhancers bearing active chromatin marks which is distinct to that of E2F1, which mostly generates promoter-specific binding. Moreover, the RelA/p65 subunit and E2F1 cistromes have limited overlap and tend to bind chromatin that is in an active state even prior to immunogenic stimulation. Finally, we found that a fraction of the E2F1 cistrome is recruited by NF-κΒ near pro-inflammatory genes following LPS stimulation in immune cell types. Full article
(This article belongs to the Special Issue NF-kB Signaling in Cellular Responses to Threats, Cancer Development and Therapy)
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26 pages, 4054 KiB  
Article
Canonical NF-κB Promotes Lung Epithelial Cell Tumour Growth by Downregulating the Metastasis Suppressor CD82 and Enhancing Epithelial-to-Mesenchymal Cell Transition
by Eugenia Roupakia, Evangelia Chavdoula, Georgia Karpathiou, Giannis Vatsellas, Dimitrios Chatzopoulos, Angeliki Mela, Jennifer M. Gillette, Katharina Kriegsmann, Mark Kriegsmann, Anna Batistatou, Anna Goussia, Kenneth B. Marcu, Emmanouil Karteris, Apostolos Klinakis and Evangelos Kolettas
Cancers 2021, 13(17), 4302; https://doi.org/10.3390/cancers13174302 - 26 Aug 2021
Cited by 2 | Viewed by 3226
Abstract
Background: The development of non-small cell lung cancer (NSCLC) involves the progressive accumulation of genetic and epigenetic changes. These include somatic oncogenic KRAS and EGFR mutations and inactivating TP53 tumour suppressor mutations, leading to activation of canonical NF-κB. However, the mechanism(s) by which [...] Read more.
Background: The development of non-small cell lung cancer (NSCLC) involves the progressive accumulation of genetic and epigenetic changes. These include somatic oncogenic KRAS and EGFR mutations and inactivating TP53 tumour suppressor mutations, leading to activation of canonical NF-κB. However, the mechanism(s) by which canonical NF-κB contributes to NSCLC is still under investigation. Methods: Human NSCLC cells were used to knock-down RelA/p65 (RelA/p65KD) and investigate its impact on cell growth, and its mechanism of action by employing RNA-seq analysis, qPCR, immunoblotting, immunohistochemistry, immunofluorescence and functional assays. Results: RelA/p65KD reduced the proliferation and tumour growth of human NSCLC cells grown in vivo as xenografts in immune-compromised mice. RNA-seq analysis identified canonical NF-κB targets mediating its tumour promoting function. RelA/p65KD resulted in the upregulation of the metastasis suppressor CD82/KAI1/TSPAN27 and downregulation of the proto-oncogene ROS1, and LGR6 involved in Wnt/β-catenin signalling. Immunohistochemical and bioinformatics analysis of human NSCLC samples showed that CD82 loss correlated with malignancy. RelA/p65KD suppressed cell migration and epithelial-to-mesenchymal cell transition (EMT), mediated, in part, by CD82/KAI1, through integrin-mediated signalling involving the mitogenic ERK, Akt1 and Rac1 proteins. Conclusions: Canonical NF-κB signalling promotes NSCLC, in part, by downregulating the metastasis suppressor CD82/KAI1 which inhibits cell migration, EMT and tumour growth. Full article
(This article belongs to the Special Issue NF-kB Signaling in Cellular Responses to Threats, Cancer Development and Therapy)
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20 pages, 4981 KiB  
Article
TRAF6 Phosphorylation Prevents Its Autophagic Degradation and Re-Shapes LPS-Triggered Signaling Networks
by Julia Busch, Rita Moreno, Laureano de la Vega, Vera Vivian Saul, Susanne Bacher, Felix von Zweydorf, Marius Ueffing, Axel Weber, Christian Johannes Gloeckner, Uwe Linne, Michael Kracht and Michael Lienhard Schmitz
Cancers 2021, 13(14), 3618; https://doi.org/10.3390/cancers13143618 - 19 Jul 2021
Cited by 4 | Viewed by 2775
Abstract
The ubiquitin E3 ligase TNF Receptor Associated Factor 6 (TRAF6) participates in a large number of different biological processes including innate immunity, differentiation and cell survival, raising the need to specify and shape the signaling output. Here, we identify a lipopolysaccharide (LPS)-dependent increase [...] Read more.
The ubiquitin E3 ligase TNF Receptor Associated Factor 6 (TRAF6) participates in a large number of different biological processes including innate immunity, differentiation and cell survival, raising the need to specify and shape the signaling output. Here, we identify a lipopolysaccharide (LPS)-dependent increase in TRAF6 association with the kinase IKKε (inhibitor of NF-κB kinase subunit ε) and IKKε-mediated TRAF6 phosphorylation at five residues. The reconstitution of TRAF6-deficient cells, with TRAF6 mutants representing phosphorylation-defective or phospho-mimetic TRAF6 variants, showed that the phospho-mimetic TRAF6 variant was largely protected from basal ubiquitin/proteasome-mediated degradation, and also from autophagy-mediated decay in autolysosomes induced by metabolic perturbation. In addition, phosphorylation of TRAF6 and its E3 ligase function differentially shape basal and LPS-triggered signaling networks, as revealed by phosphoproteome analysis. Changes in LPS-triggered phosphorylation networks of cells that had experienced autophagy are partially dependent on TRAF6 and its phosphorylation status, suggesting an involvement of this E3 ligase in the interplay between metabolic and inflammatory circuits. Full article
(This article belongs to the Special Issue NF-kB Signaling in Cellular Responses to Threats, Cancer Development and Therapy)
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Review

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21 pages, 3985 KiB  
Review
Monitoring the Levels of Cellular NF-κB Activation States
by Johanna Meier-Soelch, Christin Mayr-Buro, Jana Juli, Lisa Leib, Uwe Linne, Jan Dreute, Argyris Papantonis, M. Lienhard Schmitz and Michael Kracht
Cancers 2021, 13(21), 5351; https://doi.org/10.3390/cancers13215351 - 26 Oct 2021
Cited by 16 | Viewed by 3810
Abstract
The NF-κB signaling system plays an important regulatory role in the control of many biological processes. The activities of NF-κB signaling networks and the expression of their target genes are frequently elevated in pathophysiological situations including inflammation, infection, and cancer. In these conditions, [...] Read more.
The NF-κB signaling system plays an important regulatory role in the control of many biological processes. The activities of NF-κB signaling networks and the expression of their target genes are frequently elevated in pathophysiological situations including inflammation, infection, and cancer. In these conditions, the outcome of NF-κB activity can vary according to (i) differential activation states, (ii) the pattern of genomic recruitment of the NF-κB subunits, and (iii) cellular heterogeneity. Additionally, the cytosolic NF-κB activation steps leading to the liberation of DNA-binding dimers need to be distinguished from the less understood nuclear pathways that are ultimately responsible for NF-κB target gene specificity. This raises the need to more precisely determine the NF-κB activation status not only for the purpose of basic research, but also in (future) clinical applications. Here we review a compendium of different methods that have been developed to assess the NF-κB activation status in vitro and in vivo. We also discuss recent advances that allow the assessment of several NF-κB features simultaneously at the single cell level. Full article
(This article belongs to the Special Issue NF-kB Signaling in Cellular Responses to Threats, Cancer Development and Therapy)
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14 pages, 727 KiB  
Review
Attribution of NF-κB Activity to CHUK/IKKα-Involved Carcinogenesis
by Xin Li and Yinling Hu
Cancers 2021, 13(6), 1411; https://doi.org/10.3390/cancers13061411 - 19 Mar 2021
Cited by 21 | Viewed by 3377
Abstract
Studies analyzing human cancer genome sequences and genetically modified mouse models have extensively expanded our understanding of human tumorigenesis, even challenging or reversing the dogma of certain genes as originally characterized by in vitro studies. Inhibitor-κB kinase α (IKKα), which is encoded by [...] Read more.
Studies analyzing human cancer genome sequences and genetically modified mouse models have extensively expanded our understanding of human tumorigenesis, even challenging or reversing the dogma of certain genes as originally characterized by in vitro studies. Inhibitor-κB kinase α (IKKα), which is encoded by the conserved helix-loop-helix ubiquitous kinase (CHUK) gene, is first identified as a serine/threonine protein kinase in the inhibitor-κB kinase complex (IKK), which is composed of IKKα, IKKβ, and IKKγ (NEMO). IKK phosphorylates serine residues 32 and 36 of IκBα, a nuclear factor-κB (NF-κB) inhibitor, to induce IκBα protein degradation, resulting in the nuclear translocation of NF-κB dimers that function as transcriptional factors to regulate immunity, infection, lymphoid organ/cell development, cell death/growth, and tumorigenesis. NF-κB and IKK are broadly and differentially expressed in the cells of our body. For a long time, the idea that the IKK complex acts as a direct upstream activator of NF-κB in carcinogenesis has been predominately accepted in the field. Surprisingly, IKKα has emerged as a novel suppressor for skin, lung, esophageal, and nasopharyngeal squamous cell carcinoma, as well as lung and pancreatic adenocarcinoma (ADC). Thus, Ikkα loss is a tumor driver in mice. On the other hand, lacking the RANKL/RANK/IKKα pathway impairs mammary gland development and attenuates oncogene- and chemical carcinogen-induced breast and prostate tumorigenesis and metastasis. In general, NF-κB activation leads one of the major inflammatory pathways and stimulates tumorigenesis. Since IKKα and NF-κB play significant roles in human health, revealing the interplay between them greatly benefits the diagnosis, treatment, and prevention of human cancer. In this review, we discuss the intriguing attribution of NF-κB to CHUK/IKKα-involved carcinogenesis. Full article
(This article belongs to the Special Issue NF-kB Signaling in Cellular Responses to Threats, Cancer Development and Therapy)
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20 pages, 2345 KiB  
Review
Targeting NF-κB Signaling for Multiple Myeloma
by Ada Hang-Heng Wong, Eun Myoung Shin, Vinay Tergaonkar and Wee-Joo Chng
Cancers 2020, 12(8), 2203; https://doi.org/10.3390/cancers12082203 - 6 Aug 2020
Cited by 24 | Viewed by 5620
Abstract
Multiple myeloma (MM) is the second most common hematologic malignancy in the world. Even though survival rates have significantly risen over the past years, MM remains incurable, and is also far from reaching the point of being managed as a chronic disease. This [...] Read more.
Multiple myeloma (MM) is the second most common hematologic malignancy in the world. Even though survival rates have significantly risen over the past years, MM remains incurable, and is also far from reaching the point of being managed as a chronic disease. This paper reviews the evolution of MM therapies, focusing on anti-MM drugs that target the molecular mechanisms of nuclear factor kappa B (NF-κB) signaling. We also provide our perspectives on contemporary research findings and insights for future drug development. Full article
(This article belongs to the Special Issue NF-kB Signaling in Cellular Responses to Threats, Cancer Development and Therapy)
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