Apo2L/TRAIL: apoptosis signaling, biology, and potential for cancer therapy.
Apo2 ligand or tumor necrosis factor (TNF)-related apoptosis-inducing ligand (Apo2L/TRAIL) is one of several members of the TNF gene superfamily that induce apoptosis through engagement of death receptors. Apo2L/TRAIL is unusual as compared to any other cytokine as it interacts with a complex system of receptors: two pro-apoptotic death receptors and three anti-apoptotic decoys. This protein has generated tremendous excitement as a potential tumor-specific cancer therapeutic because, as a stable soluble trimer, it selectively induces apoptosis in many transformed cells but not in normal cells. Transcriptional activation of Apo2L/TRAIL by interferons (IFNs) through specific regulatory elements in its promoter, and possibly by a number of other cytokines, reveals its possible involvement in the activation of natural killer cells, cytotoxic T lymphocytes, and dendritic cells. In this review, we focus on the apoptosis signaling pathways stimulated by Apo2L/TRAIL, summarize what is known to date about the physiological role of this ligand and the potential for its application to cancer therapy.
Almasan
Alexandru
A
Department of Cancer Biology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, OH 44195, USA. almasaa@ccf.org
Ashkenazi
Avi
A
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins / Q000502:physiology; D006801:Humans; D007372:Interferons / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008954:Models, Biological; D016328:NF-kappa B / Q000502:physiology; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D011506:Proteins / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000502:physiology*; D014777:Virus Diseases / Q000276:immunology; D051636:X-Linked Inhibitor of Apoptosis Protein
D051017:Apoptosis Regulatory Proteins; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D002352:Carrier Proteins; C506387:Cflar protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C505653:TNFSF10 protein, human; C505654:Tnfsf10 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D007372:Interferons