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Does "death receptor" signaling play a role in tumorigenesis and cancer therapy?
1The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
Abstract:
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.
Insights
Apoptosis, or programmed cell death, is vital for development and health. Understanding its molecular control is key to treating diseases like cancer and improving therapies.
Area of Science:
- Molecular Biology
- Cell Biology
- Biochemistry
Background:
- Apoptosis (programmed cell death) is crucial for multicellular organism development and function.
- Dysregulation of apoptosis is linked to diseases including cancer, autoimmunity, and degenerative disorders.
- Apoptosis regulation influences tumor cell sensitivity to cancer therapies.
Purpose of the Study:
- To review the molecular control of apoptosis.
- To discuss the controversy surrounding the role of death receptors in chemotherapy- and radiation-induced apoptosis.
Main Methods:
- Review of existing literature on apoptosis pathways.
- Analysis of experimental data from transgenic and knockout mouse models.
- Discussion of molecular mechanisms underlying apoptosis signaling.
Main Results:
- Caspases (cysteine proteases) are essential effectors in all apoptosis pathways.
- Distinct caspases and adaptor molecules mediate different apoptosis-inducing signals (e.g., death receptor, cytokine withdrawal, DNA damage).
- Evidence challenges the model that chemotherapeutic drugs and gamma-radiation induce apoptosis solely via death receptor activation.
Conclusions:
- Molecular control of apoptosis involves complex, regulated pathways.
- Further research is needed to clarify the precise mechanisms of apoptosis induction by various stimuli, particularly in cancer therapy.