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

作　　者：Caifeng Chen Yanxin Liul Dexian Zheng 

机构地区：[1]National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, 5 Dong Dan San Tiao, Beijing 100005, China

出　　处：《Cell Research》2009年第8期984-995,共12页细胞研究（英文版）

基　　金：Acknowledgments We thank Dr Shimin Hu for his generous gifts of constructs. This work was partially supported by National Natural Science Foundation of China （Grant Nos. 30571687 and 30721063） and by State Key Basic Research Program of China （Grant No. 2007CB507404）.

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 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-κB 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 Jnrkat leukemia cells. These data provide novel information on the DR5-mediated ceil death-signaling path- way and may shed new light on effective strategies for leukemia and solid tumor therapies.

关 键 词：AD5-10 ROS .INK DR5 TRAIL 

分 类 号：Q945.78[生物学—植物学] O614.33[理学—无机化学]