Does "death receptor" signaling play a role in tumorigenesis and cancer therapy?
Physiological cell death, known as apoptosis, is an evolutionarily conserved process that is required for normal development and function of multicellular organisms. Abnormalities in cell death control are implicated as a cause or contributing factor in a range of diseases, including cancer, autoimmunity, and degenerative disorders. Importantly, the propensity of a cell to undergo apoptosis is one of the determinants of the sensitivity of tumor cells to antineoplastic therapy. Apoptosis can be triggered by stress-induced signals that arise from within the doomed cell or by signals that are elicited by binding of extracellular "death ligands" to their "death receptors." Cysteine proteases have been recognized as essential effectors of all pathways to apoptosis. Experiments with transgenic mice and gene knockout mice have shown that different caspases and their adaptor molecules are needed for "death receptor" signaling and apoptotic pathways elicited by cytokine withdrawal, DNA damage, or corticosteroids. These differences allow the pathways to be regulated by distinct inhibitors. It has been published that chemotherapeutic drugs and gamma-radiation induce apoptosis by "death ligand"-mediated activation of "death receptors," but this model has been challenged. Our review discusses this controversy in the light of current knowledge of the molecular control of apoptosis.
Villunger
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The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
Strasser
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D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D015398:Signal Transduction; D019014:fas Receptor / Q000187:drug effects / Q000378:metabolism
D000970:Antineoplastic Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D018124:Receptors, Tumor Necrosis Factor; D019014:fas Receptor; D020169:Caspases