TNF-Related Apoptosis-Inducing Ligand: Non-Apoptotic Signalling.

TNF-related apoptosis-inducing ligand (TRAIL or Apo2 or TNFSF10) belongs to the TNF superfamily. When bound to its agonistic receptors, TRAIL can induce apoptosis in tumour cells, while sparing healthy cells. Over the last three decades, this tumour selectivity has prompted many studies aiming at evaluating the anti-tumoral potential of TRAIL or its derivatives.

Proteogenomic Characterization of Bladder Cancer Reveals Sensitivity to Apoptosis Induced by Tumor Necrosis Factor-related Apoptosis-inducing Ligand in FGFR3-mutated Tumors.

Background: Molecular understanding of muscle-invasive (MIBC) and non-muscle-invasive (NMIBC) bladder cancer is currently based primarily on transcriptomic and genomic analyses.

Objective: To conduct proteogenomic analyses to gain insights into bladder cancer (BC) heterogeneity and identify underlying processes specific to tumor subgroups and therapeutic outcomes.

Design, Setting, And Participants: Proteomic data were obtained for 40 MIBC and 23 NMIBC cases for which transcriptomic and genomic data were already available.

ptARgenOM-A Flexible Vector For CRISPR/CAS9 Nonviral Delivery.

Viral-mediated delivery of the CRISPR-Cas9 system is one the most commonly used techniques to modify the genome of a cell, with the aim of analyzing the function of the targeted gene product. While these approaches are rather straightforward for membrane-bound proteins, they can be laborious for intracellular proteins, given that selection of full knockout (KO) cells often requires the amplification of single-cell clones. Moreover, viral-mediated delivery systems, besides the Cas9 and gRNA, lead to the integration of unwanted genetic material, such as antibiotic resistance genes, introducing experimental biases.

Keeping Cell Death Alive: An Introduction into the French Cell Death Research Network.

Since the Nobel Prize award more than twenty years ago for discovering the core apoptotic pathway in , apoptosis and various other forms of regulated cell death have been thoroughly characterized by researchers around the world. Although many aspects of regulated cell death still remain to be elucidated in specific cell subtypes and disease conditions, many predicted that research into cell death was inexorably reaching a plateau. However, this was not the case since the last decade saw a multitude of cell death modalities being described, while harnessing their therapeutic potential reached clinical use in certain cases.

Evidence that BJcuL, a C-type lectin from Bothrops jararacussu venom, influences deubiquitinase activity, resulting in the accumulation of anti-apoptotic proteins in two colorectal cancer cell lines.

BJcuL is a snake venom C-type lectin (SVCTL) purified from the snake's venom Bothrops jararacussu. It has been previously demonstrated that BJcuL induces the accumulation of pro-apoptotic proteins of the extrinsic pathway, such as FADD and caspase-8, in the colorectal cancer cell line HT29, suggesting that the lectin may be able to enhance TRAIL-induced apoptosis. To test this hypothesis, we exposed two colorectal cancer cell lines, HT29 and HCT116, to increasing concentrations of BJcuL (1-20 μg/mL) in the presence or absence of TRAIL.

TRAIL Triggers CRAC-Dependent Calcium Influx and Apoptosis through the Recruitment of Autophagy Proteins to Death-Inducing Signaling Complex.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively kills various cancer cell types, but also leads to the activation of signaling pathways that favor resistance to cell death. Here, we investigated the as yet unknown roles of calcium signaling and autophagy regulatory proteins during TRAIL-induced cell death in leukemia cells. Taking advantage of the Gene Expression Profiling Interactive Analysis (GEPIA) project, we first found that leukemia patients present a unique TRAIL receptor gene expression pattern that may reflect their resistance to TRAIL.

Pharmacological Investigation of CC-LAAO, an L-Amino Acid Oxidase from Snake Venom.

Snake venom proteins, which are responsible for deadly snakebite envenomation, induce severe injuries including neurotoxicity, myotoxicity, cardiotoxicity, hemorrhage, and the disruption of blood homeostasis. Yet, many snake-venom proteins have been developed as potential drugs for treating human diseases due to their pharmacological effects. In this study, we evaluated the use of, an L-amino acid oxidase isolated from snake venom CC-LAAO, as a potential anti-glioblastoma drug, by investigating its in vivo and in vitro pharmacological effects.

Neutral Sphingomyelinase 2 Heightens Anti-Melanoma Immune Responses and Anti-PD-1 Therapy Efficacy.

Dysregulation of lipid metabolism affects the behavior of cancer cells, but how this happens is not completely understood. Neutral sphingomyelinase 2 (nSMase2), encoded by , catalyzes the breakdown of sphingomyelin to produce the anti-oncometabolite ceramide. We found that this enzyme was often downregulated in human metastatic melanoma, likely contributing to immune escape.

Grafting TRAIL through Either Amino or Carboxylic Groups onto Maghemite Nanoparticles: Influence on Pro-Apoptotic Efficiency.

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF cytokine superfamily. TRAIL is able to induce apoptosis through engagement of its death receptors DR4 and DR5 in a wide variety of tumor cells while sparing vital normal cells. This makes it a promising agent for cancer therapy.

The multifaceted role of TRAIL signaling in cancer and immunity.

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily that can lead to the induction of apoptosis in tumor or infected cells. However, activation of TRAIL signaling may also trigger nonapoptotic pathways in cancer and in nontransformed cells, that is, immune cells. Here, we review the current knowledge on noncanonical TRAIL signaling.

Marine Actinomycetes-Derived Secondary Metabolites Overcome TRAIL-Resistance via the Intrinsic Pathway through Downregulation of Survivin and XIAP.

Resistance of cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis represents the major hurdle to the clinical use of TRAIL or its derivatives. The discovery and development of lead compounds able to sensitize tumor cells to TRAIL-induced cell death is thus likely to overcome this limitation. We recently reported that marine actinomycetes' crude extracts could restore TRAIL sensitivity of the MDA-MB-231 resistant triple negative breast cancer cell line.

Cisplatin unleashes Toll-like receptor 3-mediated apoptosis through the downregulation of c-FLIP in malignant mesothelioma.

Toll-like receptor 3 (TLR3) is an immune receptor that behaves like a death receptor in tumor cells, thereby providing an original target for cancer therapy. The therapeutic potential of TLR3 targeting in malignant mesothelioma, an aggressive and incurable neoplasia of the pleura and peritoneum, has so far not been addressed. We investigated TLR3 expression and sensitivity of human mesothelioma cell lines to the synthetic dsRNA Poly(I:C), alone or in combination with cisplatin, the gold standard chemotherapy in mesothelioma.

TRAIL acts synergistically with iron oxide nanocluster-mediated magneto- and photothermia.

Targeting TRAIL (Tumor necrosis factor (TNF)-Related Apoptosis-Inducing Ligand) receptors for cancer therapy remains challenging due to tumor cell resistance and poor preparations of TRAIL or its derivatives. Herein, to optimize its therapeutic use, TRAIL was grafted onto iron oxide nanoclusters (NCs) with the aim of increasing its pro-apoptotic potential through nanoparticle-mediated magnetic hyperthermia (MHT) or photothermia (PT). : The nanovector, NC@TRAIL, was characterized in terms of size, grafting efficiency, and potential for MHT and PT.

Epigenetic Regulation of TRAIL Signaling: Implication for Cancer Therapy.

One of the main characteristics of carcinogenesis relies on genetic alterations in DNA and epigenetic changes in histone and non-histone proteins. At the chromatin level, gene expression is tightly controlled by DNA methyl transferases, histone acetyltransferases (HATs), histone deacetylases (HDACs), and acetyl-binding proteins. In particular, the expression level and function of several tumor suppressor genes, or oncogenes such as c-Myc, p53 or TRAIL, have been found to be regulated by acetylation.

Generation and characterization of novel anti-DR4 and anti-DR5 antibodies developed by genetic immunization.

Development of therapeutic antibodies in oncology has attracted much interest in the past decades. More than 30 of them have been approved and are being used to treat patients suffering from cancer. Despite encouraging results, and albeit most clinical trials aiming at evaluating monoclonal antibodies directed against TRAIL agonist receptors have been discontinued, DR4 or DR5 remain interesting targets, since these receptors are overexpressed by tumour cells and are able to trigger their death.

Release of c-FLIP brake selectively sensitizes human cancer cells to TLR3-mediated apoptosis.

Toll-like receptor 3 (TLR3) mediates innate immune responses by sensing viral dsRNA, but also induces apoptosis selectively in cancer cells. Our analysis by immunohistochemistry revealed that TLR3 is frequently overexpressed in 130 non-small cell lung cancer (NSCLC) patients' samples compared with normal bronchial epithelium (P < 0.0001, Mann-Whitney test), supporting the therapeutic potential of TLR3 ligand for this type of cancer.

Correction: DNA damage and S phase-dependent E2F1 stabilization requires the cIAP1 E3-ubiquitin ligase and is associated with K63-poly-ubiquitination on lysine 161/164 residues.

Correction to:Cell Death & Disease8, e2816 (2017); https://doi.org/10.1038/cddis.

The Ectodysplasin receptor EDAR acts as a tumor suppressor in melanoma by conditionally inducing cell death.

Ectodysplasin receptor EDAR is seen as a typical Tumor Necrosis Factor receptor (TNFR) family member known to interact with its ligand Eda-A1, and signaling mainly through the nuclear factor-kappaB (NF-κB) and c-jun N-terminal kinases pathways. Mutations in genes that encode proteins involved in EDAR transduction cascade cause anhidrotic ectodermal dysplasia. Here, we report an unexpected pro-apoptotic activity of EDAR when unbound to its ligand Eda-A1, which is independent of NF-κB pathway.

Relationship between the agonist activity of synthetic ligands of TRAIL-R2 and their cell surface binding modes.

Tumor Necrosis Factor Receptor Apoptosis Inducing Ligand (TRAIL) appears as an interesting candidate for targeted cancer therapy as it induces apoptosis in cancer cells without toxicity to normal cells. TRAIL elicits apoptosis through agonist death receptor TRAIL-R1 and TRAIL-R2 engagement. Nevertheless, recombinant soluble TRAIL and monoclonal antibodies against these receptors demonstrated insufficient efficacy in clinical trials.

Regulation of TNF-Related Apoptosis-Inducing Ligand Signaling by Glycosylation.

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.

Antibodies and Derivatives Targeting DR4 and DR5 for Cancer Therapy.

Developing therapeutics that induce apoptosis in cancer cells has become an increasingly attractive approach for the past 30 years. The discovery of tumor necrosis factor (TNF) superfamily members and more specifically TNF-related apoptosis-inducing ligand (TRAIL), the only cytokine of the family capable of eradicating selectively cancer cells, led to the development of numerous TRAIL derivatives targeting death receptor 4 (DR4) and death receptor 5 (DR5) for cancer therapy. With a few exceptions, preliminary attempts to use recombinant TRAIL, agonistic antibodies, or derivatives to target TRAIL agonist receptors in the clinic have been fairly disappointing.

TRAIL-NP hybrids for cancer therapy: a review.

Cancer is a worldwide health problem. It is now considered as a leading cause of morbidity and mortality in developed countries. In the last few decades, considerable progress has been made in anti-cancer therapies, allowing the cure of patients suffering from this disease, or at least helping to prolong their lives.

Marine actinomycete crude extracts with potent TRAIL-resistance overcoming activity against breast cancer cells.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent, as it can kill tumor cells selectively. In our search of bioactive natural products to overcome TRAIL-resistance, we isolated 47 actinomycete strains from different sediments and seawater samples collected from the Red Sea coast in Egypt and found four crude extracts (EGY1, EGY3, EGY24 and EGY34) displaying TRAIL sensitizing activity in the resistant breast cancer cell line MDA-MB-231. None of these crude extracts exhibited cytotoxic effect on normal mouse embryonic fibroblasts (MEF), with the exception of EGY34.