Disease relevance of TNFSF10

• The combination of TRAIL (approved gene symbol TNFSF10) gene therapy and 5-FU enhanced tumor suppression in vivo in nude mice bearing subcutaneous tumors established from TRAIL-resistant colon cancer cells [1].
• In this study, we investigated the tumoricidal potential of a recombinant adenovirus encoding human TNFSF10 (Ad5-TRAIL), alone and in combination with a panel of histone deacetylase inhibitors (HDACi), against the TRAIL/Apo-2L-resistant RCC line 786-O and normal human renal proximal tubule epithelial cells (RPTEC) [2].
• Apo2L/TRAIL and Bcl-2-related proteins regulate type I interferon-induced apoptosis in multiple myeloma [3].
• NF-kappaB-independent actions of sulfasalazine dissociate the CD95L- and Apo2L/TRAIL-dependent death signaling pathways in human malignant glioma cells [4].
• Relation of TNF-related apoptosis-inducing ligand (TRAIL) receptor and FLICE-inhibitory protein expression to TRAIL-induced apoptosis of melanoma [5].

Psychiatry related information on TNFSF10

• TNF-related apoptosis-inducing ligand (TRAIL) induces neuronal apoptosis in HIV-encephalopathy [6].
• Additionally, standard psychometric tests (Trail Making Test A, Mini-Mental State Examination, and Profile of Mood State test) were performed [7].
• Moreover, parkinsonian patients with the lowest scores on 'frontal' neuropsychological tests such as Stroop, Trail Making and Word Fluency, also had the lowest processing negativity [8].
• A correlation was found between ideomotor apraxia scores in PD patients and deficits in frontal lobe-related neuropsychological tasks such as the Tower of Hanoi, verbal fluency and the Trail Making Test. Furthermore, PD patients with apraxia showed higher Hamilton depression scores than non-apraxic PD patients [9].
• Women with anorexia nervosa were slower than other groups on Trail Making tasks [10].

High impact information on TNFSF10

• Most importantly, Smac peptides strongly enhanced the antitumor activity of Apo-2L/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in an intracranial malignant glioma xenograft model in vivo [11].
• Treatment of colon tumor cells deficient in DNA mismatch repair with the death-receptor ligand apo2 ligand (Apo2L)/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selected in vitro or in vivo for refractory subclones with Bax frameshift mutations including deletions at a novel site [12].
• Here we show that in NB4 acute promyelocytic leukemia cells, retinoids selective for retinoic-acid receptor-alpha induced an autoregulatory circuitry of survival programs followed by expression of the membrane-bound tumor-selective death ligand, TRAIL (tumor necrosis factor-related apoptosis-inducing ligand, also called Apo-2L) [13].
• Differential hepatocyte toxicity of recombinant Apo2L/TRAIL versions [14].
• TRAIL, also called Apo2L, is a cytotoxic protein that induces apoptosis of many transformed cell lines but not of normal tissues, even though its death domain-containing receptor, DR4, is expressed on both cell types [15].

Chemical compound and disease context of TNFSF10

• Sensitization of AIDS-Kaposi's sarcoma cells to Apo-2 ligand-induced apoptosis by actinomycin D [16].
• CCNU-dependent potentiation of TRAIL/Apo2L-induced apoptosis in human glioma cells is p53-independent but may involve enhanced cytochrome c release [17].
• Neutrophil stimulation with Mycobacterium bovis bacillus Calmette-Guerin (BCG) results in the release of functional soluble TRAIL/Apo-2L [18].
• Adriamycin sensitizes the adriamycin-resistant 8226/Dox40 human multiple myeloma cells to Apo2L/tumor necrosis factor-related apoptosis-inducing ligand-mediated (TRAIL) apoptosis [19].
• Molecular determinants of epothilone B derivative (BMS 247550) and Apo-2L/TRAIL-induced apoptosis of human ovarian cancer cells [20].

Biological context of TNFSF10

• Furthermore, IFNs and Apo2L induce cell death of CD38(+)/CD45(-/dim) plasma cells, without significant effect on nonplasma blood cells, in a caspase and Bcl-2 cleavage-dependent manner [3].
• Cell survival was significantly augmented, indicating that increased Apo2L expression contributed to radiation-induced apoptosis [21].
• We isolated 1152 bp of 5' flanking region of the Apo2L gene and a shorter fragment of 716 bp, both of which showed promoter activity driving the expression of a luciferase reporter gene; however, the response to radiation in MOLT-4 cells was lost when only 430 bp of 5' proximal flanking sequence was maintained [21].
• TRAIL/Apo2L activated caspase-8 and caspase-3, but subsequent apoptotic events such as poly(ADP-ribose) polymerase cleavage and DNA fragmentation were not observed [22].
• The closest homolog of Apo2L is CD95 (Fas/Apo1) ligand, to which it has 24% amino acid sequence identity [23].

Anatomical context of TNFSF10

• Activated human NK and CD8+ T cells express both TNF-related apoptosis-inducing ligand (TRAIL) and TRAIL receptors but are resistant to TRAIL-mediated cytotoxicity [24].
• IFNalpha-stimulated neutrophils and monocytes release a soluble form of TNF-related apoptosis-inducing ligand (TRAIL/Apo-2 ligand) displaying apoptotic activity on leukemic cells [25].
• Apo-2L-induced apoptosis was significantly inhibited in HL-60 cells that overexpressed Bcl-2 or Bcl-x(L) [26].
• Although a broad spectrum of human cancer cell lines express death receptors for Apo2L/TRAIL, many remain resistant to TRAIL/Apo2L-induced death [27].
• Increased Apo2L protein levels were found in MOLT-4 and Jurkat cells [21].

Associations of TNFSF10 with chemical compounds

• These findings indicate that treatment with etoposide, Ara-C, or doxorubicin up-regulates DR5 levels in a p53-independent manner and sensitizes human acute leukemia cells to Apo-2L-induced apoptosis [26].
• Exogenous Apo2L induced phosphatidylserine exposure on cell membranes, caspase 8 and caspase 3 activation, key markers of apoptosis, confirming that the Apo2L/DR5 pathway is functional in these cells [21].
• Apo2 ligand (Apo2L [1], also called TRAIL for tumor necrosis factor (TNF)-related apoptosis-inducing ligand [2]) belongs to the TNF family and activates apoptosis in tumor cells [28].
• AIDS-KS cells were relatively resistant to Apo-2L; however, Apo-2L and actinomycin D (Act D) used in combination synergistically potentiated the induction of cell death in nine of the 10 isolates [16].
• Also, PS-341 enhanced TRAIL (TNF-related apoptosis-inducing ligand) and TNFalpha (tumor necrosis factor alpha) induced cell death and apoptosis (two- to five-fold) in GBM cells [29].

Physical interactions of TNFSF10

• We have found that the GTP-binding protein DAP3 binds directly (with high affinity) to the death domain of TNF-related apoptosis-inducing ligand (TRAIL) receptors, and is required for TRAIL-induced apoptosis [30].
• Triggering cell death: the crystal structure of Apo2L/TRAIL in a complex with death receptor 5 [31].
• TRAIL (TNF-related apoptosis-inducing ligand) induces apoptosis in susceptible cells by binding to death receptors 4 (DR4) and 5 (DR5) [32].
• The discovery that OPG can bind to and inhibit the activity of TRAIL (TNF-related apoptosis-inducing ligand) triggered extensive research into the potential role of OPG in the regulation of tumour cell survival [33].
• Addition of the APO2L-binding decoy receptor 1 (DcR1)-Fc fusion protein inhibited the cytotoxicity by 30-70% [34].

Regulatory relationships of TNFSF10

• Antileukemic drugs increase death receptor 5 levels and enhance Apo-2L-induced apoptosis of human acute leukemia cells [26].
• These findings demonstrate that cotreatment with the N-terminus Smac/DIABLO peptide is an effective strategy to enhance apoptosis triggered by the death receptor or mitochondrial pathway and may improve the antitumor activity of Apo-2L/TRAIL and Epo B [35].
• TRAIL/Apo2L was induced in melanoma cell lines by IFN-beta and had been correlated with apoptosis induction [22].
• In the presence of IL-2, recombinant APO2L/TRAIL or cytotoxic anti-Fas monoclonal antibodies induce rather inhibition of IL-2-dependent growth and not cell death on normal human T cell blasts [36].
• Overexpression of BCL2 blocks TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in human lung cancer cells [37].

Other interactions of TNFSF10

• To determine whether Apo2L and DR5 were critical for radiation signaling to apoptosis, we stably expressed a dominant negative DR5delta-receptor in Jurkat cells [21].
• These findings indicate that up-regulation of DR4 and DR5 protein levels by treatment with paclitaxel enhances subsequent Apo-2L/TRAIL-induced apoptosis of human prostate cancer cells [38].
• Thus, Apo2L/TRAIL and TNF organize common molecular determinants in distinct signaling complexes to stimulate similar kinase pathways [39].
• In this study, we show by confocal microscopy that FasL and APO2L/TRAIL are mainly localized in lysosomal-like compartments in these cells [40].
• Cleavage of X-linked inhibitor of apoptosis following IFN-beta and TRAIL/Apo2L treatment was observed in sensitive WM9, A375, or WM3211 cells but not in resistant WM35 or WM164 cells [22].

Analytical, diagnostic and therapeutic context of TNFSF10

• We have previously shown that mesothelioma cells, resistant to most treatments, are sensitive to the combination of the death ligand tumor necrosis factor-related apoptosis inducing ligand (TRAIL/Apo2L) plus chemotherapy [41].
• All human melanoma cell lines (assessed by annexin V and TUNEL assays) were resistant to apoptosis induction by TRAIL/Apo2L protein [22].
• We show also by immunoelectron microscopy that FasL and APO2L/TRAIL are stored inside cytoplasmic compartments approximately 500 nm in diameter, with characteristics of multivesicular bodies [40].
• Administration of Apo2L/TRAIL (0.3, 1, 3, 10, and 30 mg/kg/day for 7 days via i.p. infusion) to nude mice harboring established intracranial U87 xenografts produced a significant, dose-dependent prolongation of survival versus control animals [42].
• Immunofluorescence staining demonstrated that Apo2L/TRAIL protein was abundant within the cytoplasm of NHBC and OPG was strongly expressed at the cell surface [43].

References