An agonistic monoclonal antibody against DR5 induces ROS production, sustained JNK activat

An agonistic monoclonal antibody against DR5 induces ROS production, sustained JNK activation

and Endo G release in Jurkat leukemia cells

Caifeng Chen;Yanxin Liu;Dexian Zheng

【期刊名称】《细胞研究（英文版）》 【年(卷),期】2009(019)008

【摘要】We have previously reported that AD5-10, a novel agonistic monoclonal antibody against DRS, 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 ADS-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 ADS-10. Moreover, a dominant-nega-tive form of JNK (but not of p38) enhanced NF-KB 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