CD95L

CAR T cell treatment of solid tumours is limited by poor persistence partly due to CD95 ligand (CD95L)-induced apoptosis. Both T cells and cells within the tumour microenvironment (TME) may express CD95L, triggering apoptosis in CD95-receptor-positive CAR T cells. Tonic signalling of CAR T cells may also increase CD95-dependent AICD. Because the intracellular protein c-FLIP protects T cells from AICD, we expressed c-FLIPp43 within a Her-2 targeted CAR cassette and evaluated the potential of c-FLIPp43 through in vitro functional assays and in vivo tumour-bearing xenograft model...

CD95 (Fas/APO-1) is a multifunctional cell surface receptor with antithetic roles. First described to mediate cell death, interactions of CD95 with its natural ligand, CD95L, have also been described to induce tumor-promoting signaling leading to proliferation, invasion and stem cell maintenance, mainly in cancer cells that are resistant to CD95-mediated apoptosis. While activation of CD95-mediated apoptosis in cancer cells may not be clinically practicable due to toxicity, inhibition of tumor-promoting CD95 signaling holds therapeutic potential...

Study of the initial steps of the CD95-mediated signaling pathways is a field of intense research and a long list of actors has been described in the literature. Nonetheless, the dynamism of protein-protein interactions (PPIs) occurring in the presence or absence of its natural ligand, CD95L, and the cellular distribution where these PPIs take place render it difficult to predict what will be the cellular outcome associated with the receptor engagement. Accordingly, CD95 stimulation can trigger apoptosis, necroptosis, pyroptosis, or pro-inflammatory signaling pathways such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and phosphatidylinositol-3-kinase (PI3K)...

Mobilized peripheral blood cells (MPBCs) graft and peripheral blood cells apheresis are used for bone marrow transplantation and for treatment of graft versus host disease (GvHD). We demonstrate that a short treatment of MPBCs with Fas ligand (FasL, CD95L) for 2 h using a closed automated cell processing system selectively induces apoptosis of specific donor T cells, B cells and antigen presenting cells, but, critically, not CD34+ hematopoietic stem cells and progenitors, all of which may contribute to an increased likelihood of graft survival and functionality and reduced GvHD...

The intestinal flora plays an important role in the development of many human and animal diseases. Microbiome association studies revealed the potential regulatory function of intestinal bacteria in many liver diseases, such as autoimmune hepatitis, viral hepatitis and alcoholic hepatitis. However, the key intestinal bacterial strains that affect pathological liver injury and the underlying functional mechanisms remain unclear. We found that the gut microbiota from gentamycin (Gen)-treated mice significantly alleviated concanavalin A (ConA)-induced liver injury compared to vancomycin (Van)-treated mice by inhibiting CD95 expression on the surface of hepatocytes and reducing CD95/CD95L-mediated hepatocyte apoptosis...

Extranodal NK/T-cell lymphoma is a neoplasm of NK cells or cytotoxic T cells presenting in extranodal sites, most often in the nasal cavity. The typical immunophenotypes are cCD3+, sCD3-, CD4-, CD5-, CD8-, CD16-, and CD56+ with the expression of cytotoxic molecules. Tumor subsets express NK cell receptors, CD95/CD95L, CD30, MYC, and PDL1. Virtually all the tumor cells harbor the EBV genome, which plays a key role in lymphomagenesis as an epigenetic driver. EBV-encoded oncoproteins modulate the host-cell epigenetic machinery, reprogramming the viral and host epigenomes using host epigenetic modifiers...

CD95 expression is preserved in triple-negative breast cancers (TNBCs), and CD95 loss in these cells triggers the induction of a pro-inflammatory program, promoting the recruitment of cytotoxic NK cells impairing tumor growth. Herein, we identify a novel interaction partner of CD95, Kip1 ubiquitination-promoting complex protein 2 (KPC2), using an unbiased proteomic approach. Independently of CD95L, CD95/KPC2 interaction contributes to the partial degradation of p105 (NF-κB1) and the subsequent generation of p50 homodimers, which transcriptionally represses NF-κB-driven gene expression...

Despite the potential apoptotic functions, the CD95/CD95L system can stimulate survival as well as pro-inflammatory signaling, particularly through the activation of NFκB. This holds true for the TNF/TNFR and the TRAIL/TRAILR systems. Thus, signaling pathways of these three death ligands converge, yet the specific impact of the CD95/CD95L system in this crosstalk has not been well studied. In this study, we show that gemcitabine stimulates the expression of pro-inflammatory cytokines, such as IL6 and IL8, under the influence of the CD95/CD95L system and the pharmacological inhibitor, sCD95Fc, substantially reduced the expression in two PDAC cell lines, PancTuI-luc and A818-4...

Cancer stem cells (CSCs) play an essential role in cancer development, metastasis, relapse, and resistance to treatment. In this article, the effects of three synthesized ZnO nanofluids on proliferation, apoptosis, and stemness markers of breast cancer stem-like cells are reported. The antiproliferative and apoptotic properties of ZnO nanoparticles were evaluated on breast cancer stem-like cell-enriched mammospheres by MTS assay and flowcytometry, respectively. The expression of stemness markers, including WNT1, NOTCH1, β-catenin, CXCR4, SOX2, and ALDH3A1 was assessed by real-time PCR...

Although CD95L (also known as FasL) is still predominantly considered as a death ligand that induces apoptosis in infected and transformed cells, substantial evidence indicate that it can also trigger non-apoptotic signaling pathways whose pathophysiological roles remain to be fully elucidated. The transmembrane ligand CD95L belongs to the tumor necrosis factor (TNF) superfamily. After cleavage by metalloprotease, its soluble form (s-CD95L) fails to trigger the apoptotic program but instead induces signaling pathways promoting the aggressiveness of certain inflammatory disorders such as autoimmune diseases and cancers...

Background: Chronic viral hepatitis B (HBV) is characterised by progressive hepatocyte destruction and T-cell depletion. The mechanisms of the CD95-CD95 ligand (CD95L) signalling pathway during this chronic disease and the cirrhotic process remains unclear. Objective: We evaluated the involvement of the CD95-CD95L receptor-ligand system in T-cell depletion and hepatic cytolysis in patients with chronic HBV. Methods: This was a cross-sectional study conducted from September to December 2018 at the Yaoundé General Hospital, Cameroon...

The ability of FasL/CD95L to induce apoptosis in various Fas/CD95-expressing cells has been described in the context of hematopoiesis or thymic elimination of self-reactive T cells and resolution of an acute immune response under physiological conditions. At the same time, non-apoptotic CD95 activation is widely described in cancer and shown to stimulate invasiveness of cancer cells, promote cancer progression as well as stemness of cancer cells. This paper puts emphasis on the evolving understanding of expression and the non-apoptotic activities of the CD95/CD95L signaling pathway on the function of tumor cells, tumor microenvironment and immune cells...

Cancer cells develop tactics to circumvent the interventions by desensitizing themselves to interventions. Amongst many, the principle routes of desensitization include a) activation of survival pathways (e.g. NF-kB, PARP) and b) downregulation of cell death pathways (e.g. CD95/CD95L). As a result, it requires high therapeutic dose to achieve tumor regression which, in turn damages normal cells through the collateral effects. Methods are needed to sensitize the low and non-responsive resistant tumor cells including cancer stem cells (CSCs) in order to evoke a better response from the current treatments...

The development of efficient combinatorial treatments is one of the key tasks in modern anti-cancer therapies. An apoptotic signal can either be induced by activation of death receptors (DR) (extrinsic pathway) or via the mitochondria (intrinsic pathway). Cancer cells are characterized by deregulation of both pathways. Procaspase-8 activation in extrinsic apoptosis is controlled by c-FLIP proteins. We have recently reported the small molecules FLIPinB/FLIPinBγ targeting c-FLIPL in the caspase-8/c-FLIPL heterodimer...

PURPOSE: Cardiotoxicity is one of the most commonly encountered adverse effects observed alongside the therapeutic use of doxorubicin (DOX), thus curbing its therapeutic utility. METHODS: The current study was conducted to evaluate the cardioprotective effect of gabapentin (Gaba), a Ca + 2 channel blocker with emerging pharmacological merits, against DOX-induced cardiotoxicity. Gaba was orally administered at two dose levels (10 and 30 mg/kg) for 21 days parallel to DOX injection...

Toxic epidermal necrolysis (TEN) represents a rare drug-induced autoimmune reaction with delayed-type hypersensitivity that initiates the process of developing massive keratinocyte apoptosis, dominantly in the dermoepidermal junction. Although the etiopathophysiology has not yet been fully elucidated, the binding of Fas ligand (FasL, CD95L) to the Fas receptor (CD95) was shown to play a key role in the induction of apoptosis in this syndrome. The knowledge of the role of immunoglobulin G (IgG) in inhibition of Fas-mediated apoptosis contributed to the introduction of i...

BACKGROUND: Cancer Stem Cells (CSCs) play an important role in various stages of cancer development, advancement, and therapy resistance. Ketoprofen-RGD has been revealed to act as an anti-cancer agent against some tumors. OBJECTIVE: We aimed to explore the effects of a novel Ketoprofen-RGD compound on the suppression of Breast Cancer Stem-like Cells (BCSCs) and their parental cells. METHODS: Mammospheres were developed from MCF-7 cells and assessed by CSC surface markers through flowcytometry...

Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumour necrosis factor (TNF) superfamily which mainly induces apoptosis of tumour cells and transformed cell lines with no systemic toxicity, whereas they share high sequence homology with TNF and CD95L. These unique effects of TRAIL have made it an important molecule in oncology research. However, the research on TRAIL-related antineoplastic agents has lagged behind and has been limited by the extensive drug resistance in cancer cells...

Fas ligand (First apoptosis signal ligand, FasL, also known as CD95L) is the common executioner of apoptosis within the tumor necrosis factor (TNF) superfamily. We aimed to induce functional FasL expression in transduced cells using an adenovirus vector, which has the advantage of strong and transient induction of the gene included in the adenoviral genome. Here, we report that the adenovirus carrying a truncated FasL gene, named FasL minigene, encoding the full-length FasL protein (Ad-gFasL) is more efficient than the adenovirus carrying FasL cDNA (Ad-cFasL) in the induction of FasL expression in transduced cells...

CD95 is a pre-ligand-associated transmembrane (TM) receptor. The interaction with its ligand CD95L brings to a next level its aggregation and triggers different signaling pathways, leading to cell motility, differentiation or cell death. This diversity of biological responses associated with a unique receptor devoid of enzymatic property raises the question of whether different ligands exist, or whether the fine-tuned control of CD95 aggregation and conformation, its distribution within certain plasma membrane sub-domains or the pattern of post-translational modifications account for this such broad-range of cell signaling...