This article serves as an introduction to the collection of reviews on nuclear factor-kappaB (NF-kappaB). It provides an overview of the discovery and current status of NF-kappaB as a research topic. Described are the structures, activities and regulation of the proteins in the NF-kappaB family of transcription factors. NF-kappaB signaling is primarily regulated by inhibitor kappaB (IkappaB) proteins and the IkappaB kinase complex through two major pathways: the canonical and non-canonical NF-kappaB pathways. The organization and focus of articles included in the following reviews are described, as well as likely future areas of research interest on NF-kappaB.

Introduction to NF-kappaB: players, pathways, perspectives.

One of the primary physiological roles of nuclear factor-kappa B (NF-κB) is in the immune system. In particular, NF-κB family members control the transcription of cytokines and antimicrobial effectors as well as genes that regulate cellular differentiation, survival and proliferation, thereby regulating various aspects of innate and adaptive immune responses. In addition, NF-κB also contributes to the development and survival of the cells and tissues that carry out immune responses in mammals. This review, therefore, describes the role of the NF-κB pathway in the development and functioning of the immune system.

NF-kappaB and the immune response.

The nuclear factor κB (NF-κB) signalling pathway has been implicated in cancer development and progression, as well as in resistance to chemotherapy and radiation therapy. In this Perspective, Baud and Karin explore the therapeutic potential of targeting NF-κB in cancer, and discuss the challenges posed by this approach. Nuclear factor κB (NF-κB) transcription factors have a key role in many physiological processes such as innate and adaptive immune responses, cell proliferation, cell death, and inflammation. It has become clear that aberrant regulation of NF-κB and the signalling pathways that control its activity are involved in cancer development and progression, as well as in resistance to chemotherapy and radiotherapy. This article discusses recent evidence from cancer genetics and cancer genome studies that support the involvement of NF-κB in human cancer, particularly in multiple myeloma. The therapeutic potential and benefit of targeting NF-κB in cancer, and the possible complications and pitfalls of such an approach, are explored.

https://www.hal.inserm.fr/inserm-00352349/document

Is NF-κB a good target for cancer therapy? Hopes and pitfalls

It is only recently that the full importance of nuclear factor-κB (NF-κB) signalling to cancer development has been understood. Although much attention has focused on the upstream pathways leading to NF-κB activation, it is now becoming clear that the inhibitor of NF-κB kinases (IKKs), which regulate NF-κB activation, have many independent functions in tissue homeostasis and normal immune function that could compromise the clinical utility of IKK inhibitors. Therefore, if the NF-κB pathway is to be properly exploited as a target for both anticancer and anti-inflammatory drugs, it is appropriate to reconsider the complex roles of the individual NF-κB subunits.

The diverse and complex roles of NF-κB subunits in cancer

The generation of reactive oxygen species (ROS) and an altered redox status are common biochemical aspects in cancer cells. ROS can react with the polyunsaturated fatty acids of lipid membranes and induce lipid peroxidation. The end products of lipid peroxidation, 4-hydroxynonenal (HNE), have been considered to be a second messenger of oxidative stress. Beyond ROS involvement in carcinogenesis, increased ROS level can inhibit tumor cell growth. Indeed, in tumors in advanced stages, a further increase of oxidative stress, such as that occurs when using several anticancer drugs and radiation therapy, can overcome the antioxidant defenses of cancer cells and drive them to apoptosis. High concentrations of HNE can also induce apoptosis in cancer cells. However, some cells escape the apoptosis induced by chemical or radiation therapy through the adaptation to intrinsic oxidative stress which confers drug resistance. This paper is focused on recent advances in the studies of the relation between oxidative stress, lipid peroxidation products, and cancer progression with particular attention to the pro-oxidant anticancer agents and the drug-resistant mechanisms, which could be modulated to obtain a better response to cancer therapy.

/pdf/oxidative-stress-and-lipid-peroxidation-products-in-cancer-4lkjscnwon.pdf

Oxidative stress and lipid peroxidation products in cancer progression and therapy.

The nuclear factor-kappaB (NF-kappaB) transcription factors have emerged as major regulators of programmed cell death (PCD) whether via apoptosis or necrosis. In this context, NF-kappaB's activity has important ramifications for normal tissue development, homoeostasis and the physiological functions of various cell systems including the immune, hepatic, epidermal and nervous systems. However, improper regulation of PCD by NF-kappaB can have severe pathologic consequences, ranging from neurodegeneration to cancer, where its activity often precludes effective therapy. Although NF-kappaB generally protects cells by inducing the expression genes encoding antiapoptotic and antioxidizing proteins, its role in apoptosis and necrosis can vary markedly in different cell contexts, and NF-kappaB can sensitize cells to death-inducing stimuli in some instances. This article describes our current knowledge of the role of NF-kappaB in apoptosis and necrosis, and focuses on the many advances since we last reviewed this rapidly evolving topic in Oncogene 3 years ago. There has been substantial progress in understanding NF-kappaB's mode of action in apoptosis and necrosis and the mechanisms that regulate its anti- vs proapoptotic activities. These recent developments shed new light on the role of NF-kappaB in many disease conditions including tumor development, tumor progression and anticancer treatment.

Current insights into the regulation of programmed cell death by NF-kappaB.

The Rel/NF-kappaB transcription factors are key regulators of programmed cell death (PCD). Their activity has significant physiological relevance for normal development and homeostasis in various tissues and important pathological consequences are associated with aberrant NF-kappaB activity, including hepatocyte apoptosis, neurodegeneration, and cancer. While NF-kappaB is best characterized for its protective activity in response to proapoptotic stimuli, its role in suppressing programmed necrosis has come to light more recently. NF-kappaB most commonly antagonizes PCD by activating the expression of antiapoptotic proteins and antioxidant molecules, but it can also promote PCD under certain conditions and in certain cell types. It is therefore important to understand the pathways that control NF-kappaB activation in different settings and the mechanisms that regulate its anti- vs pro-death activities. Here, we review the role of NF-kappaB in apoptotic and necrotic PCD, the mechanisms involved, and how its activity in the cell death response impacts cancer development, progression, and therapy. Given the role that NF-kappaB plays both in tumor cells and in the tumor microenvironment, recent findings underscore the NF-kappaB signaling pathway as a promising target for cancer prevention and treatment.

Regulation of Programmed Cell Death by NF-κB and its Role in Tumorigenesis and Therapy

The Rel/NF-kappaB transcription factors are constitutively activated in many human cancers. The Rel proteins in this family are implicated in leukemia/lymphomagenesis, but the mechanism is not completely understood. Previous studies showed that the transcription activation domains (TADs) of the viral oncoprotein v-Rel and its cellular Rel/NF-kappaB homologues c-Rel and RelA are key determinants of their different transforming activities in primary lymphocytes. Substitution of a Rel TAD for that of RelA conferred a strong transforming phenotype upon RelA, which otherwise failed to transform cells. To gain insights into protein interactions that influence cell transformation by the Rel TADs, we identified factors that interact with the TAD of v-Rel, the most oncogenic member of the Rel/NF-kappaB family. We report that the coactivator for transcription factors AP-1 and estrogen receptors, CAPERalpha, interacts with the v-Rel TAD and potently synergizes v-Rel-mediated transactivation. Importantly, coexpression of CAPERalpha markedly reduced and delayed v-Rel's transforming activity in primary lymphocytes, whereas a dominant-negative mutant enhanced the kinetics of v-Rel-mediated transformation. Furthermore, small interfering RNA-mediated knockdown of CAPERalpha in v-Rel-transformed lymphocytes significantly enhanced colony formation in soft agar. Since the potency of Rel-mediated transactivation is an important determinant of lymphocyte transformation, as is Rel's ability to induce transcriptional repression, these data suggest that CAPERalpha's interaction with the Rel TAD could modulate Rel/NF-kappaB's transforming activity by facilitating expression or dampening repression of specific gene subsets important for oncogenesis. Overall, this study identifies CAPERalpha as a new transcriptional coregulator for v-Rel and reveals an important role in modulating Rel's oncogenic activity.

CAPERα Is a Novel Rel-TAD-Interacting Factor That Inhibits Lymphocyte Transformation by the Potent Rel/NF-κB Oncoprotein v-Rel

The Rel/NF-KB transcription factors are renowned for their fundamental contribution to normal immune, inflammatory and acute phase responses. A growing body of evidence also underscores their important role in the control of cellular gene expres­ sion, cell proliferation and apoptosis. Thus, it comes as no surprise that sustained Rel/NF-ICB activity has emerged as a hallmark of many human cancers. Experimental evidence indicates a strong correlation between the transcriptional activity of Rel/NF-KB and its role in malignant cell transformation. The important role of NF-KB in the control of the apoptotic response also supports its participation in the resistance of tumor cells to therapeutic treatment. This review focuses on the mechanisms that underUe the contribution of Rel/NF-KB to cancer and high­ lights how appreciation of its role in this context has evolved from a bird s eye view to a true recognition of its RELevant function in oncogenesis.

Molecular Basis of Oncogenesis by NF-κB: From a Bird's Eye View to a RELevant Role in Cancer

The coronavirus disease 2019 (COVID-19) infection has most commonly led to patients presenting with pulmonary disease, including severe acute respiratory syndrome. However, in about 14-53% of patients with a newly diagnosed COVID-19 infection, the liver is the organ most drastically affected, as opposed to the lungs. In patients with preexisting liver damage, the first symptom of a COVID-19 infection may come from worsening liver failure such as hepatic encephalopathy or worsening ascites. This case report highlights this unusual presentation of a COVID-19 infection in a patient with preexisting alcoholic liver cirrhosis. We report this case to heed warning that acutely worsening liver failure may be the first presenting symptom of a superimposed COVID-19 infection on preexisting liver disease.

/pdf/rapid-turn-from-cirrhosis-to-encephalopathy-following-covid-26olr1ul.pdf

Jui Dutta

Papers

Current insights into the regulation of programmed cell death by NF-kappaB.

Regulation of Programmed Cell Death by NF-κB and its Role in Tumorigenesis and Therapy

CAPERα Is a Novel Rel-TAD-Interacting Factor That Inhibits Lymphocyte Transformation by the Potent Rel/NF-κB Oncoprotein v-Rel

Molecular Basis of Oncogenesis by NF-κB: From a Bird's Eye View to a RELevant Role in Cancer

Rapid Turn From Cirrhosis to Encephalopathy Following COVID-19 Infection: A Cautionary Tale