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Apoptosis and drug response
1Department of Molecular Pharmacology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Abstract:
Recent investigation further defines the role of p53 and of signaling events upstream and downstream of p53 in apoptosis following drug-induced DNA damage. The transcription factors NF-kappaB and AP-1 can be activated, and then directly transactivate FasL in response to chemotherapeutic agents. Death receptors for FasL (Fas) and for TRAIL (DR4, DR5) are emerging as important regulators of drug-induced apoptosis in human cancers, mediated by caspase activation. Apoptosis has been accepted as the predominant mechanism of drug-induced cell death in preclinical experimental models and in clinically sensitive tumors. However, drug-induced cell death can include acute or delayed apoptosis, necrosis, or a delayed mitotic death, and require further delineation for their relative contribution to tumor responses in vivo.
Insights
Drug-induced DNA damage triggers apoptosis via p53 and transcription factors activating FasL. Understanding these pathways, including death receptors, is crucial for cancer treatment responses.
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Research
Background:
- p53 plays a critical role in apoptosis following DNA damage.
- Transcription factors like NF-kappaB and AP-1 are involved in drug-induced apoptosis.
- Death receptors (Fas, DR4, DR5) and their ligands (FasL, TRAIL) are key in cancer cell death.
Purpose of the Study:
- To further define the role of p53 and its associated signaling pathways in apoptosis after drug-induced DNA damage.
- To investigate the activation of transcription factors NF-kappaB and AP-1 and their role in FasL transactivation.
- To explore the significance of death receptors (Fas, DR4, DR5) in drug-induced apoptosis in human cancers.
Main Methods:
- Analysis of p53 signaling pathways.
- Investigation of transcription factor activation (NF-kappaB, AP-1).
- Study of FasL transactivation and death receptor signaling.
Main Results:
- p53 and signaling events upstream and downstream of p53 are critical in drug-induced apoptosis.
- NF-kappaB and AP-1 are activated by chemotherapeutic agents and transactivate FasL.
- Death receptors Fas, DR4, and DR5 mediate caspase activation and apoptosis in response to FasL and TRAIL.
Conclusions:
- Apoptosis is a primary mechanism of drug-induced cell death in preclinical models and sensitive tumors.
- Drug-induced cell death encompasses apoptosis, necrosis, and mitotic death, requiring further in vivo delineation.
- Understanding these molecular pathways is essential for optimizing cancer therapy.