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Cell surface Death Receptor signaling in normal and cancer cells
Nesrin Ozören1, Wafik S El-Deiry
1Department of Medicine, University of Pennsylvania School of Medicine, CRB 437A, 415 Curie Blvd., Philadelphia, PA 19104, USA.
Abstract:
The extrinsic cell death pathway is initiated upon ligand-receptor interactions at the cell surface including FAS ligand-FAS/APO1, TNF-TNF receptors, and TRAIL-TRAIL receptors. Abnormalities of various components of these pathways have been identified in human cancer including loss of FAS expression, deletion or loss of TRAIL receptor DR4, mutation of TRAIL receptor DR5, overexpression of TRAIL decoy TRID or overexpression of Fas decoy, as well as overexpression of the caspase activation inhibitor, FLIP. Death ligands have been explored as potential therapeutics in cancer therapy with some limitations in the case of FAS and TNF due to toxicities. TRAIL remains promising as a therapeutic and has potential for combination with chemo- or radio-therapy. The death receptor signaling pathways include cross-talk with the mitochondrial pathway and can in some cases be influenced by mitochondrial membrane potential changes or NF-kappaB. FLIP and BCL-XL expression may reduce sensitivity of cancer cells to combination therapies.
Insights
Extrinsic cell death pathways, involving FAS, TNF, and TRAIL ligands, are crucial in cancer. TRAIL shows therapeutic promise, especially combined with other treatments, despite challenges with FAS and TNF.
Area of Science:
- Cellular biology
- Molecular oncology
- Immunology
Background:
- The extrinsic cell death pathway is triggered by ligand-receptor interactions like FAS ligand-FAS/APO1, TNF-TNF receptors, and TRAIL-TRAIL receptors.
- Aberrations in these pathways, such as altered receptor expression or decoy molecules, are implicated in human cancers.
Purpose of the Study:
- To explore the role of extrinsic cell death pathways in cancer.
- To evaluate the therapeutic potential of death ligands, particularly TRAIL, in cancer treatment.
Main Methods:
- Review of literature on extrinsic cell death pathways and their components.
- Analysis of genetic alterations and expression levels of key proteins in cancer.
Main Results:
- Dysregulation of FAS, TNF, and TRAIL pathway components is common in human cancers.
- While FAS and TNF ligands face toxicity limitations, TRAIL remains a promising therapeutic agent.
- TRAIL's efficacy may be enhanced through combination therapies with chemotherapy or radiotherapy.
Conclusions:
- TRAIL-based therapies, potentially combined with other treatments, offer a promising avenue for cancer treatment.
- Understanding cross-talk with mitochondrial pathways and the influence of inhibitors like FLIP is crucial for optimizing combination therapies.