ORIGINAL ARTICLE

Cell Research (2009): 1-12
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An agonistic monoclonal antibody against DR5 induces ROS production, sustained JNK activation and Endo G release in Jurkat leukemia cells

Caifeng Chen, Yanxin Liu and Dexian Zheng

Correspondence: Dexian Zheng, Tel: +86-10-6529 6409; Fax: +86-10-6510 5102 E-mail: zhengdx@pumc.edu.cn or zhengdx@tom.com

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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-B 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.

Cell Research advance online publication 26 May 2009; doi: 10.1038/cr.2009.60

Keywords: AD5–10, ROS, JNK, DR5, TRAIL