The kiss of death: promises and failures of death receptors and ligands in cancer therapy.
Death receptors and their ligands exert important regulatory functions in the maintenance of tissue homeostasis and the physiological regulation of programmed cell death. Currently, six different death receptors are known including tumor necrosis factor (TNF) receptor-1, CD95 (Fas/APO-1), TNF receptor-related apoptosis-mediating protein (TRAMP), TNF-related apoptosis-inducing ligand (TRAIL) receptor-1 and -2, and death receptor-6 (DR6). The signaling pathways by which these receptors induce apoptosis are similar and rely on oligomerization of the receptor by death ligand binding, recruitment of an adapter protein through homophilic interaction of cytoplasmic domains, and subsequent activation of an inducer caspase which initiates execution of the cell death programme. The ability of these receptors and their ligands to kill malignant cells was discovered early and helped to coin the term 'tumor necrosis factor' for the first identified death ligand. This review summarizes the current and rapidly expanding knowledge about the signaling pathways triggered by death receptor/ligand systems, their potency in experimental cancer therapy, and their therapeutic limitations, especially regarding their toxicity for non-malignant cells.
Daniel
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PT
Department of Hematology, Oncology, and Tumor Immunology, University Medical Center Charité, Humboldt University, Berlin, Germany.
Wieder
T
T
Sturm
I
I
Schulze-Osthoff
K
K
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015703:Antigens, CD / Q000502:physiology; D017209:Apoptosis; D002352:Carrier Proteins / Q000502:physiology; D020169:Caspases / Q000502:physiology; D053222:Fas Ligand Protein; D053200:Fas-Associated Death Domain Protein; D006801:Humans; D008562:Membrane Glycoproteins / Q000502:physiology*; D009369:Neoplasms / Q000628:therapy*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D053219:Receptors, Tumor Necrosis Factor, Member 25; D047888:Receptors, Tumor Necrosis Factor, Type I; D019014:fas Receptor / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; D002352:Carrier Proteins; C505533:FADD protein, human; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D053200:Fas-Associated Death Domain Protein; D008562:Membrane Glycoproteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053219:Receptors, Tumor Necrosis Factor, Member 25; D047888:Receptors, Tumor Necrosis Factor, Type I; C505639:TNFRSF10B protein, human; C114109:TNFRSF21 protein, human; C506033:TNFRSF25 protein, human; D019014:fas Receptor; D020169:Caspases