Explore the vast range of titles available.

Tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) can induce apoptosis in a wide variety of cancer cells, both in vitro and in vivo, importantly without killing any essential normal cells. These findings formed the basis for the development of TRAIL-receptor agonists (TRAs) for cancer therapy. However, clinical trials conducted with different types of TRAs have, thus far, afforded only limited therapeutic benefit, as either the respectively chosen agonist showed insufficient anticancer activity or signs of toxicity, or the right TRAIL-comprising combination therapy was not employed. Therefore, in this review we will discuss molecular determinants of TRAIL resistance, the most promising TRAIL-sensitizing agents discovered to date and, importantly, whether any of these could also prove therapeutically efficacious upon cancer relapse following conventional first-line therapies. We will also discuss the more recent progress made with regards to the clinical development of highly active non-immunogenic next generation TRAs. Based thereupon, we next propose how TRAIL resistance might be successfully overcome, leading to the possible future development of highly potent, cancer-selective combination therapies that are based on our current understanding of biology TRAIL-induced cell death. It is possible that such therapies may offer the opportunity to tackle one of the major current obstacles to effective cancer therapy, namely overcoming chemo- and/or targeted-therapy resistance. Even if this were achievable only for certain types of therapy resistance and only for particular types of cancer, this would be a significant and meaningful achievement.

APO2L/TRAIL (TNF-related apoptosis-inducing ligand) induces death of tumor cells through two agonist receptors, TRAIL-R1 and TRAIL-R2. We demonstrate here that N-linked glycosylation (N-glyc) plays also an important regulatory role for TRAIL-R1-mediated and mouse TRAIL receptor (mTRAIL-R)-mediated apoptosis, but not for TRAIL-R2, which is devoid of N-glycans. Cells expressing N-glyc-defective mutants of TRAIL-R1 and mouse TRAIL-R were less sensitive to TRAIL than their wild-type counterparts. Defective apoptotic signaling by N-glyc-deficient TRAIL receptors was associated with lower TRAIL receptor aggregation and reduced DISC formation, but not with reduced TRAIL-binding affinity. Our results also indicate that TRAIL receptor N-glyc impacts immune evasion strategies. The cytomegalovirus (CMV) UL141 protein, which restricts cell-surface expression of human TRAIL death receptors, binds with significant higher affinity TRAIL-R1 lacking N-glyc, suggesting that this sugar modification may have evolved as a counterstrategy to prevent receptor inhibition by UL141. Altogether our findings demonstrate that N-glyc of TRAIL-R1 promotes TRAIL signaling and restricts virus-mediated inhibition.

The galectin 3 binding protein (LGALS3BP, also known as 90K) is a ubiquitous multifunctional secreted glycoprotein originally identified in cancer progression. It remains unclear how 90K functions in innate immunity during viral infections. In this study, we found that viral infections resulted in elevated levels of 90K. Further studies demonstrated that 90K expression suppressed virus replication by inducing IFN and pro-inflammatory cytokine production. Upon investigating the mechanisms behind this event, we found that 90K functions as a scaffold/adaptor protein to interact with TRAF6, TRAF3, TAK1 and TBK1. Furthermore, 90K enhanced TRAF6 and TRAF3 ubiquitination and served as a specific ubiquitination substrate of TRAF6, leading to transcription factor NF-κB, IRF3 and IRF7 translocation from the cytoplasm to the nucleus. Conclusions: 90K is a virus-induced protein capable of binding with the TRAF6 and TRAF3 complex, leading to IFN and pro-inflammatory production.

Tumor necrosis-factor related apoptosis-inducing ligand, also known as TRAIL or APO2L (Apo-2 ligand), is a cytokine of the TNF superfamily acknowledged for its ability to trigger selective apoptosis in tumor cells while being relatively safe towards normal cells. Its binding to its cognate agonist receptors, namely death receptor 4 (DR4) and/or DR5, can induce the formation of a membrane-bound macromolecular complex, coined DISC (death-signaling inducing complex), necessary and sufficient to engage the apoptotic machinery. At the very proximal level, TRAIL DISC formation and activation of apoptosis is regulated both by antagonist receptors and by glycosylation. Remarkably, though, despite the fact that all membrane-bound TRAIL receptors harbor putative glycosylation sites, only pro-apoptotic signaling through DR4 and DR5 has, so far, been found to be regulated by N- and O-glycosylation, respectively. Because putative N-glycosylation sequons and O-glycosylation sites are also found and conserved in all these receptors throughout all animal species (in which these receptors have been identified), glycosylation is likely to play a more prominent role than anticipated in regulating receptor/receptor interactions or trafficking, ultimately defining cell fate through TRAIL stimulation. This review aims to present and discuss these emerging concepts, the comprehension of which is likely to lead to innovative anticancer therapies.

Since its discovery in 1975, TNFα has been a subject of intense study as it plays significant roles in both immunity and cancer. Such attention is well deserved as TNFα is unique in its engagement of pleiotropic signaling via its two receptors: TNFR1 and TNFR2. Extensive research has yielded mechanistic insights into how a single cytokine can provoke a disparate range of cellular responses, from proliferation and survival to apoptosis and necrosis. Understanding the intracellular signaling pathways induced by this single cytokine via its two receptors is key to further revelation of its exact functions in the many disease states and immune responses in which it plays a role. In this review, we describe the signaling complexes formed by TNFR1 and TNFR2 that lead to each potential cellular response, namely, canonical and non-canonical NF-κB activation, apoptosis and necrosis. This is followed by a discussion of data from in vivo mouse and human studies to examine the differential impacts of TNFR1 versus TNFR2 signaling.

Cell death in human diseases is often a consequence of disrupted cellular homeostasis. If cell death is prevented without restoring cellular homeostasis, it may lead to a persistent dysfunctional and pathological state. Although mechanisms of cell death have been thoroughly investigated 1 – 3 , it remains unclear how homeostasis can be restored after inhibition of cell death. Here we identify TRADD 4 – 6 , an adaptor protein, as a direct regulator of both cellular homeostasis and apoptosis. TRADD modulates cellular homeostasis by inhibiting K63-linked ubiquitination of beclin 1 mediated by TRAF2, cIAP1 and cIAP2, thereby reducing autophagy. TRADD deficiency inhibits RIPK1-dependent extrinsic apoptosis and proteasomal stress-induced intrinsic apoptosis. We also show that the small molecules ICCB-19 and Apt-1 bind to a pocket on the N-terminal TRAF2-binding domain of TRADD (TRADD-N), which interacts with the C-terminal domain (TRADD-C) and TRAF2 to modulate the ubiquitination of RIPK1 and beclin 1. Inhibition of TRADD by ICCB-19 or Apt-1 blocks apoptosis and restores cellular homeostasis by activating autophagy in cells with accumulated mutant tau, α-synuclein, or huntingtin. Treatment with Apt-1 restored proteostasis and inhibited cell death in a mouse model of proteinopathy induced by mutant tau(P301S). We conclude that pharmacological targeting of TRADD may represent a promising strategy for inhibiting cell death and restoring homeostasis to treat human diseases. The adaptor protein TRADD is a regulator of both cellular homeostasis and apoptosis, and represents a potential therapeutic target for human diseases.

Background Acne vulgaris (AV) is a chronic inflammatory skin condition affecting the pilosebaceous unit, commonly presenting as comedones, papules, pustules, or nodules on the face, upper limbs, torso, and back, with comedones formation being the primary pathology leading to disfiguring inflammation, hyperpigmentation, scarring, and psychological impact. Aim The purpose of this study was to investigate the significance of two genetic variants in the promoter region of the tumor necrosis factor‐alpha (TNF‐α) gene and their association with insulin resistance (IR) in acne patients. To understand how these variants contribute to AV and its associated IR. Subjects and methods An analytical cross‐sectional study with a case‐control design and research evaluation was carried out on 87 AV patients and 73 healthy volunteers. The medical histories of both groups were obtained, as well as the severity and duration of inflammation among acne sufferers, as well as demographic data. Biochemical analysis was performed on both sets of participants, including fasting blood glucose levels, insulin levels while fasting, IR, and serum TNF‐α. PCR‐RFLP analysis identified −863 G > A (rs1800630) and −308 G > A (rs1800629) variations, and real‐time PCR analysis evaluated TNF‐α gene expression in both patients and healthy people. Results Acne patients exhibited significantly higher levels of IR, fasting glucose, fasting insulin, serum TNF‐α, and TNF‐α folding change, when compared to healthy controls. The co‐dominant model for −863 G > A and −308 G > A variants exhibited significant variations between the two groups. Severe acne patients who had the A/A genotype for −308 variants exhibited higher levels of IR, serum TNF‐α, and TNF‐α folding change. Highly significant positive linear correlation between IR, serum TNF‐α, and TNF‐α folding change in severe AV. Conclusion There is a correlation between AV, especially severe acne, and the −863 G > A and −308 G > A polymorphism, which influences TNF‐α gene expression and serum TNF‐α levels.

The first Food and Drug Administration-(FDA)-approved drugs were small, chemically-manufactured and highly active molecules with possible off-target effects, followed by protein-based medicines such as antibodies. Conventional antibodies bind a specific protein and are becoming increasingly important in the therapeutic landscape. A very prominent class of biologicals are the anti-tumor necrosis factor (TNF) drugs that are applied in several inflammatory diseases that are characterized by dysregulated TNF levels. Marketing of TNF inhibitors revolutionized the treatment of diseases such as Crohn’s disease. However, these inhibitors also have undesired effects, some of them directly associated with the inherent nature of this drug class, whereas others are linked with their mechanism of action, being pan-TNF inhibition. The effects of TNF can diverge at the level of TNF format or receptor, and we discuss the consequences of this in sepsis, autoimmunity and neurodegeneration. Recently, researchers tried to design drugs with reduced side effects. These include molecules with more specificity targeting one specific TNF format or receptor, or that neutralize TNF in specific cells. Alternatively, TNF-directed biologicals without the typical antibody structure are manufactured. Here, we review the complications related to the use of conventional TNF inhibitors, together with the anti-TNF alternatives and the benefits of selective approaches in different diseases.

TLR4 signals via MyD88 and TRIF to activate proinflammatory cytokine and type I interferon responses. Karin and colleagues show that different ubiquitination of TRAF3 via K48 or K63 dictates the ensuing immune response. Balanced production of type I interferons and proinflammatory cytokines after engagement of Toll-like receptors (TLRs), which signal through adaptors containing a Toll–interleukin 1 receptor (TIR) domain, such as MyD88 and TRIF, has been proposed to control the pathogenesis of autoimmune disease and tumor responses to inflammation. Here we show that TRAF3, a ubiquitin ligase that interacts with both MyD88 and TRIF, regulated the production of interferon and proinflammatory cytokines in different ways. Degradative ubiquitination of TRAF3 during MyD88-dependent TLR signaling was essential for the activation of mitogen-activated protein kinases (MAPKs) and production of inflammatory cytokines. In contrast, TRIF-dependent signaling triggered noncanonical TRAF3 self-ubiquitination that activated the interferon response. Inhibition of degradative ubiquitination of TRAF3 prevented the expression of all proinflammatory cytokines without affecting the interferon response.

Key Points Tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a potent stimulator of apoptosis, and tumour cells are significantly more sensitive to TRAIL-induced apoptosis than normal cells. Although the molecular basis for the tumour-selective activity of TRAIL remains to be fully defined, the TRAIL pathway is an attractive therapeutic target for the treatment of cancer. In addition to triggering a pro-apoptotic signal through activation of caspases, TRAIL can activate diverse intracellular signalling pathways involving NFκB, phosphoinositoide 3-kinase (PI3K) and mitogen activated protein kinase (MAPK) family proteins that can stimulate cell survival and proliferation. TRAIL is an important immune effector molecule in the surveillance and elimination of developing tumours. Moreover, genetic lesions in various components of the TRAIL pathway have been found in human tumour samples, suggesting that inactivation of the TRAIL pathway and/or escape from TRAIL-mediated immunosurveillance might have an important role in tumour onset and progression. In preclinical trials, recombinant forms of TRAIL and agonistic anti-TRAIL receptor antibodies can have single-agent activity against TRAIL-sensitive tumour cells in vitro and in vivo . These agents can synergize with chemotherapeutic drugs and novel molecular therapeutic agents to more effectively kill TRAIL-sensitive tumour cells and TRAIL-resistant tumours. Early-phase clinical trials using recombinant TRAIL and agonistic anti-TRAIL receptor antibodies indicate that these agents can be delivered safely and are generally well-tolerated. Although some objective anti-tumour responses have been reported with these agents as monotherapies, they probably hold greater promise for further clinical development when used in combination with other cancer treatments. Tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) receptors (TRAILR1 and TRAILR2) are promising targets for cancer therapy: both recombinant TRAIL and monoclonal antibodies that target these receptors have entered clinical trials. How are these agents faring? What are the current stumbling blocks? Triggering of tumour cell apoptosis is the foundation of many cancer therapies. Death receptors of the tumour necrosis factor (TNF) superfamily have been largely characterized, as have the signals that are generated when these receptors are activated. TNF-related apoptosis-inducing ligand (TRAIL) receptors (TRAILR1 and TRAILR2) are promising targets for cancer therapy. Herein we review what is known about the molecular control of TRAIL-mediated apoptosis, the role of TRAIL in carcinogenesis and the potential therapeutic utility of recombinant TRAIL and agonistic antibodies against TRAILR1 and TRAILR2.