We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
The Fas/Fas Ligand Apoptotic Pathway Is Involved in Abrin-Induced Apoptosis.
- Authors
Saxena, Nandita; Yadav, Preeti; Kumar, Om
- Abstract
Editor’s Highlight: Abrin is a potential agent of bioterrorism and has been used as a chemotherapeutic agent. It is a ribosome inactivating protein, structurally related to but more potent than ricin. Successful antidotes depend on knowledge about toxic mechanisms of action, but presently those intoxicated with abrin can receive only supportive medical care, owing in large part to a lack of knowledge about its mechanism of action. While it has been known that abrin inactivates protein synthesis and activates endogenous apoptotic pathways, other and potentially more specific biological events have not been identified. Here, these authors report important new findings demonstrating that abrin exposure also results in activation of the exogenous apoptotic Fas/Fas ligand pathway. Findings like these may lead to improved therapeutic interventions and more tailored application in cancer chemotherapy. – John LipscombAbrin is a plant glycoprotein toxin from the seeds of Abrus precatorius, sharing similarity in structure and properties with ricin. Abrin is highly toxic, with an estimated human fatal dose of 0.1–1 µg/kg, causing death after accidental or intentional poisoning. It is a potent biological toxin warfare agent. There is no chemical antidote available against the abrin. The elucidation of molecular mechanism of abrin-induced cell death is important for development of therapy. Intrinsic pathway-mediated apoptosis has been well established in abrin-induced cell death. However, the detailed mechanism especially extrinsic receptor-mediated pathway remains uncharacterized. To assess whether some of the apoptosis known to occur after abrin exposure might be mediated by Fas/Fas ligand (Fas L) interactions, we analyzed effect of abrin on Fas pathway in Jurkat cells. Here, we report that activation of the Fas pathway is involved in abrin-induced apoptosis. Following treatment of abrin, Fas L was induced, which stimulated the Fas pathway by cross-linking Fas receptor (Fas R). Apoptosis was mediated by cleavage of the Fas R proximal caspase-8 and the downstream caspase-3, resulting in activation of the prototype caspase substrate poly-(ADP-ribose) polymerase and caspase-activated DNase. Blocking Fas L/Fas R interaction by using Fas inhibitor reduced abrin-induced apoptosis, further confirms involvement of Fas pathway. Activation of components of Fas pathway and caspases upon abrin treatment was also found in splenocytes in mice. Our findings offer new perspective for understanding the fundamental mechanism in abrin-induced apoptotic mechanism and may have implication in developing novel therapeutic strategies in the management for abrin-induced complications.
- Subjects
LIGANDS (Biochemistry); APOPTOSIS; ABRIN; DRUG therapy; BIOTERRORISM; CASPASES; CELL death; RIBOSOME-inactivating proteins
- Publication
Toxicological Sciences, 2013, Vol 135, Issue 1, p103
- ISSN
1096-6080
- Publication type
Article
- DOI
10.1093/toxsci/kft139