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

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling".

Deadline for manuscript submissions: closed (30 June 2021) | Viewed by 17865

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Dr. Evangelos Kolettas

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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
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Prof. Dr. Kenneth B. Marcu

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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
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Dr. Johannes A. Schmid

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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
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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 Cells–Cancers 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

Professor Kenneth B. Marcu

Professor Johannes A. Schmid

Guest Editors

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Keywords

NF-kappa B subunits
I-kappa B 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 cells metabolism

Related Special Issue

NF-kB Signaling in Cellular Responses to Threats, Cancer Development and Therapy in Cancers (7 articles)

Published Papers (11 papers)

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Research

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23 pages, 8451 KiB

Open AccessArticle

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://0-doi-org.brum.beds.ac.uk/10.3390/cancers14246164 - 14 Dec 2022

Cited by 4 | Viewed by 2672

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 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

Open AccessArticle

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://0-doi-org.brum.beds.ac.uk/10.3390/cancers14205047 - 14 Oct 2022

Cited by 1 | Viewed by 1876

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 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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21 pages, 6138 KiB

Open AccessFeature PaperArticle

Anti-Inflammatory Extract from Soil Algae Chromochloris zofingiensis Targeting TNFR/NF-κB Signaling at Different Levels

by Peter D. Leitner, Thomas Jakschitz, Ronald Gstir, Stefan Stuppner, Sebastian Perkams, Maren Kruus, Alexander Trockenbacher, Christoph Griesbeck, Günther K. Bonn, Lukas A. Huber and Taras Valovka

Cells 2022, 11(9), 1407; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11091407 - 21 Apr 2022

Cited by 9 | Viewed by 3362

Abstract

Inflammatory skin diseases, including atopic dermatitis (AD) and psoriasis, are increasing in populations worldwide. The treatment of patients with AD and other forms of skin inflammation is mainly based on the use of topical corticosteroids or calcineurin inhibitors, which can cause significant side effects with long-term use. Therefore, there is a great need for the development of more effective and less toxic anti-inflammatory agents suitable for the treatment of chronic skin lesions. Here, we screened a number of strains from the ASIB 505 terrestrial algae collection and identified a green algae Chromochloris zofingiensis with pronounced anti-inflammatory properties. We found that a crude nonpolar extract of C. zofingiensis (ID name NAE_2022C), grown upon nitrogen deprivation, acts as a bioactive substance by inhibiting TNFR/NF-κB responses in human skin keratinocyte HaCaT cells. We also found that NAE_2022C suppressed the secretion of pro-inflammatory cytokine tumor necrosis factor α (TNFα) and several Th1- and Th2-related chemokines in a reconstituted human epidermis. The TNFR/NF-κB pathway analysis showed multiple inhibitory effects at different levels and disclosed a direct targeting of IKKβ by the extract. Bioassay-guided fractionation followed by high-resolution mass spectrometry detected diacylglyceryl-trimethylhomoserine (DGTS), Lyso-DGTS (LDGTS), 5-phenylvaleric acid, theophylline and oleamide as leading metabolites in the active fraction of NAE_2022C. Further analysis identified betaine lipid DGTS (32:0) as one of the active compounds responsible for the NAE_2022C-mediated NF-κB suppression. Overall, this study presents an approach for the isolation, screening, and identification of anti-inflammatory secondary metabolites produced by soil algae. 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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13 pages, 2200 KiB

Open AccessArticle

Zinc Ameliorates the Osteogenic Effects of High Glucose in Vascular Smooth Muscle Cells

by Laura A. Henze, Misael Estepa, Burkert Pieske, Florian Lang, Kai-Uwe Eckardt, Ioana Alesutan and Jakob Voelkl

Cells 2021, 10(11), 3083; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10113083 - 09 Nov 2021

Cited by 13 | Viewed by 1948

Abstract

In diabetic patients, medial vascular calcification is common and associated with increased cardiovascular mortality. Excessive glucose concentrations can activate the nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-kB) and trigger pro-calcific effects in vascular smooth muscle cells (VSMCs), which may actively augment vascular calcification. Zinc is able to mitigate phosphate-induced VSMC calcification. Reduced serum zinc levels have been reported in diabetes mellitus. Therefore, in this study the effects of zinc supplementation were investigated in primary human aortic VSMCs exposed to excessive glucose concentrations. Zinc treatment was found to abrogate the stimulating effects of high glucose on VSMC calcification. Furthermore, zinc was found to blunt the increased expression of osteogenic and chondrogenic markers in high glucose-treated VSMCs. High glucose exposure was shown to activate NF-kB in VSMCs, an effect that was blunted by additional zinc treatment. Zinc was further found to increase the expression of TNFα-induced protein 3 (TNFAIP3) in high glucose-treated VSMCs. The silencing of TNFAIP3 was shown to abolish the protective effects of zinc on high glucose-induced NF-kB-dependent transcriptional activation, osteogenic marker expression, and the calcification of VSMCs. Silencing of the zinc-sensing receptor G protein-coupled receptor 39 (GPR39) was shown to abolish zinc-induced TNFAIP3 expression and the effects of zinc on high glucose-induced osteogenic marker expression. These observations indicate that zinc may be a protective factor during vascular calcification in hyperglycemic conditions. 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

Open AccessArticle

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://0-doi-org.brum.beds.ac.uk/10.3390/cancers13174302 - 26 Aug 2021

Cited by 2 | Viewed by 3155

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 canonical NF-κB contributes to NSCLC is still under investigation. Methods: Human NSCLC cells were used to knock-down RelA/p65 (RelA/p65^KD) 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/p65^KD 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/p65^KD 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/p65^KD 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

Open AccessArticle

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://0-doi-org.brum.beds.ac.uk/10.3390/cancers13143618 - 19 Jul 2021

Cited by 4 | Viewed by 2707

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 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

Open AccessReview

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://0-doi-org.brum.beds.ac.uk/10.3390/cancers13215351 - 26 Oct 2021

Cited by 16 | Viewed by 3587

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, 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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21 pages, 2333 KiB

Open AccessReview

Inhibition of Cellular and Animal Inflammatory Disease Models by NF-κB Inhibitor DHMEQ

by Jun Ma, Yuyang Zhang, Takeshi Sugai, Tetsuo Kubota, Hiroshi Keino, Magdy El-Salhy, Michitaka Ozaki and Kazuo Umezawa

Cells 2021, 10(9), 2271; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10092271 - 01 Sep 2021

Cited by 10 | Viewed by 3060

Abstract

General inflammatory diseases include skin inflammation, rheumatoid arthritis, inflammatory bowel diseases, sepsis, arteriosclerosis, and asthma. Although these diseases have been extensively studied, most of them are still difficult to treat. Meanwhile, NF-κB is a transcription factor promoting the expression of many inflammatory mediators. NF-κB is likely to be involved in the mechanism of most inflammatory diseases. We discovered a specific NF-κB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), about 20 years ago by molecular design from a natural product. It directly binds to and inactivates NF-κB components. It has been widely used to suppress cellular and animal inflammatory disease models and was shown to be potent in vivo anti-inflammatory activity without any toxicity. We have prepared ointment of DHMEQ for the treatment of severe skin inflammation. It inhibited inflammatory cytokine expressions and lowered the clinical score in mouse models of atopic dermatitis. Intraperitoneal (IP) administration of DHMEQ ameliorated various disease models of inflammation, such as rheumatoid arthritis, sepsis, and also graft rejection. It has been suggested that inflammatory cells in the peritoneal cavity would be important for most peripheral inflammation. In the present review, we describe the synthesis, mechanism of action, and cellular and in vivo anti-inflammatory activities and discuss the clinical use of DHMEQ for inflammatory diseases. 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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23 pages, 2340 KiB

Open AccessReview

Challenges with Methods for Detecting and Studying the Transcription Factor Nuclear Factor Kappa B (NF-κB) in the Central Nervous System

by Marina Mostafizar, Claudia Cortes-Pérez, Wanda Snow, Jelena Djordjevic, Aida Adlimoghaddam and Benedict C. Albensi

Cells 2021, 10(6), 1335; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10061335 - 28 May 2021

Cited by 12 | Viewed by 8005

Abstract

The transcription factor nuclear factor kappa B (NF-κB) is highly expressed in almost all types of cells. NF-κB is involved in many complex biological processes, in particular in immunity. The activation of the NF-κB signaling pathways is also associated with cancer, diabetes, neurological disorders and even memory. Hence, NF-κB is a central factor for understanding not only fundamental biological presence but also pathogenesis, and has been the subject of intense study in these contexts. Under healthy physiological conditions, the NF-κB pathway promotes synapse growth and synaptic plasticity in neurons, while in glia, NF-κB signaling can promote pro-inflammatory responses to injury. In addition, NF-κB promotes the maintenance and maturation of B cells regulating gene expression in a majority of diverse signaling pathways. Given this, the protein plays a predominant role in activating the mammalian immune system, where NF-κB-regulated gene expression targets processes of inflammation and host defense. Thus, an understanding of the methodological issues around its detection for localization, quantification, and mechanistic insights should have a broad interest across the molecular neuroscience community. In this review, we summarize the available methods for the proper detection and analysis of NF-κB among various brain tissues, cell types, and subcellular compartments, using both qualitative and quantitative methods. We also summarize the flexibility and performance of these experimental methods for the detection of the protein, accurate quantification in different samples, and the experimental challenges in this regard, as well as suggestions to overcome common challenges. 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

Open AccessReview

Attribution of NF-κB Activity to CHUK/IKKα-Involved Carcinogenesis

by Xin Li and Yinling Hu

Cancers 2021, 13(6), 1411; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13061411 - 19 Mar 2021

Cited by 21 | Viewed by 3271

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 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

Open AccessReview

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://0-doi-org.brum.beds.ac.uk/10.3390/cancers12082203 - 06 Aug 2020

Cited by 24 | Viewed by 5502

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 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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