Does "death receptor" signaling play a role in tumorigenesis and cancer therapy?

Physiological cell death, known as apoptosis, is an evolutionarily conserve d process that is required for normal development and function of multicell ular organisms. Abnormalities in cell death control are implicated as a cau se or contributing factor in a range of diseases, including cancer, autoimm unity, and degenerative disorders. Importantly, the propensity of a cell to undergo apoptosis is one of the determinants of the sensitivity of tumor c ells to antineoplastic therapy. Apoptosis can be triggered by stress-induce d signals that arise from within the doomed cell or by signals that are eli cited by binding of extracellular "death ligands" to their "death receptors ." Cysteine proteases have been recognized as essential effecters of all pa thways to apoptosis. Experiments with transgenic mice and gene knockout mic e 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 pa thways to be regulated by distinct inhibitors. It has been published that c hemotherapeutic drugs and gamma-radiation induce apoptosis by "death ligand "-mediated activation of "death receptors," but this model has been challen ged. Our review discusses this controversy in the light of current knowledg e of the molecular control of apoptosis.