An agonistic monoclonal antibody against DR5 induces ROS production, sustained JNK activation and Endo G release in Jurkat leukemia cells.

Abstract

We have previously reported that AD5-10, a novel agonistic monoclonal antibody against DR5, possessed a strong cytotoxic activity in various tumor cells, via induction of caspase-dependent and -independent signaling pathways. The present study further demonstrates that reactive oxygen species (ROS) were generated in abundance in Jurkat leukemia cells upon AD5-10 stimulation and that ROS accumulation subsequently evoked sustained activation of c-Jun N-terminal kinase (JNK), loss of mitochondrial membrane potential, and release of endonuclease G (Endo G) from mitochondria into the cytosol. The reducing agent, N-acetylcysteine (NAC), effectively inhibited the sustained activation of JNK, release of Endo G, and cell death in Jurkat cells treated by AD5-10. Moreover, a dominant-negative form of JNK (but not of p38) enhanced NF-kappaB activation, suppressed caspase-8 recruitment in death-inducing signaling complexes (DISCs), and reduced adverse effects on mitochondria, thereby inhibiting AD5-10-induced cell death in Jurkat leukemia cells. These data provide novel information on the DR5-mediated cell death-signaling pathway and may shed new light on effective strategies for leukemia and solid tumor therapies.

• Authors: Caifeng Chen, Yanxin Liu, Dexian Zheng
• Journal: Cell research (Cell Res) Vol. 19 Issue 8 Pg. 984-95 (Aug 2009) ISSN: 1748-7838 [Electronic] England
• PMID: 19468286 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• NF-kappa B
• Reactive Oxygen Species
• Receptors, TNF-Related Apoptosis-Inducing Ligand
• JNK Mitogen-Activated Protein Kinases
• Endodeoxyribonucleases
• endonuclease G
• Caspase 8
• Acetylcysteine

Topics

• Acetylcysteine (pharmacology)
• Antibodies, Monoclonal (pharmacology)
• Apoptosis
• Caspase 8 (metabolism)
• Cell Line, Tumor
• Endodeoxyribonucleases (metabolism)
• Humans
• JNK Mitogen-Activated Protein Kinases (metabolism)
• Jurkat Cells
• Leukemia (enzymology, metabolism)
• Membrane Potential, Mitochondrial
• Mitochondria (metabolism)
• NF-kappa B (metabolism)
• Reactive Oxygen Species (metabolism)
• Receptors, TNF-Related Apoptosis-Inducing Ligand (agonists, metabolism)
• Signal Transduction