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

Chen, Caifeng; Liu, Yanxin; Zheng, Dexian

doi:10.1038/cr.2009.60

Cited by 17 publications

(14 citation statements)

References 46 publications

(83 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The apoptotic morphological features of dying cells caused by exposure to KD548-Fc and little effects of the necrosis inhibitor necrostatin-1 and autophagy inhibitors (3-methyladenine and chloroquine) on KD54-Fc-induced cell death exclude necrosis and autophagy as the primary cell death mechanisms of KD548-Fc. In good agreement with our results, ROSmediated sustained JNK activation was responsible for the caspase-independent apoptotic cell death of Jurkat cells mediated by an agonistic mAb against DR5 (20). The protein RIP1 is required for CD95L-, TNF␣-, and TRAIL-induced necrotic cell death in human cells (29) and the ROS-mediated necrotic cell death by TNF␣ in mouse fibroblasts (9).…”

Section: Discussionsupporting

confidence: 77%

“…Because the antioxidant NAC significantly inhibited KD548-Fc-mediated cell death, we measured the time course of intracellular accumulation of ROS by 2Ј,7Ј-dichlorofluorescein diacetate staining and then flow cytometry (20). KD548-Fctreated HeLa and Jurkat cells displayed substantially amplified ROS levels, exhibiting more than 2-fold higher ROS levels over the time course up to 40 h compared with those of untreated control cells (Fig.…”

Section: Kd548-fc-induced Apoptosis Is Mediated By Ros-dependentmentioning

confidence: 99%

“…Measurement of ROS Production-The ROS level was detected by using 2Ј,7Ј-dichlorofluorescein diacetate (Invitrogen), following the manufacturer's protocol (20). Cells (3 ϫ 10 5 cells) were treated with KD548-Fc or TRAIL for different time periods, collected, and washed with PBS.…”

Section: Light Microscopy and Transmission Electronmentioning

confidence: 99%

See 2 more Smart Citations

Death Receptors 4 and 5 Activate Nox1 NADPH Oxidase through Riboflavin Kinase to Induce Reactive Oxygen Species-mediated Apoptotic Cell Death

Park

Lee

Kim

et al. 2012

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background:We report the cell death mechanism of KD548-Fc, an Fc-fused DR4/DR5 dual-specific Kringle domain variant. Results: KD548-Fc-stimulated DR4/DR5 activate Nox1 NADPH oxidase to generate superoxide anion, leading to reactive oxygen species-mediated apoptotic cell death. Conclusion: DR4/DR5 have the capability to activate Nox1. Significance: Our results provide a new signaling pathway of DR4/DR5, distinct from the conventional apoptosis pathway.

show abstract

Section: Discussionsupporting

confidence: 77%

Section: Kd548-fc-induced Apoptosis Is Mediated By Ros-dependentmentioning

confidence: 99%

See 1 more Smart Citation

Death Receptors 4 and 5 Activate Nox1 NADPH Oxidase through Riboflavin Kinase to Induce Reactive Oxygen Species-mediated Apoptotic Cell Death

Park

Lee

Kim

et al. 2012

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…For example, a recent study demonstrates a novel DR5 (TRAIL R-2) monoclonal antibody, AD5-10, generates ROS production in Jurkat leukemia cells. As a result of the ROS production, JNK is activated, and mitochondrial membrane potential is lost, and intracellular GSH and oxidized glutathione (GSSG) levels are decreased, and endonuclease G is translocated from the mitochondria into the cytosol, all of which lead to the selective apoptosis of the leukemia cells in vitro (45). Moreover, Jurkat, a human acute lymphocytic leukemia cell line ( Jurkat T-ALL), transfected with a dominant-negative (DN) form of JNK (but not of p38), enhanced NFjB activation, reduced caspase-8 in death-inducing signaling complexes (DISCs), and reduced damage to mitochondria, thereby inhibiting AD5-10-induced cell death in the DN-mutant cells.…”

Section: Cancer and Metastasismentioning

confidence: 99%

Redox Regulation of T-Cell Function: From Molecular Mechanisms to Significance in Human Health and Disease

Kesarwani

Murali

Al-Khami

et al. 2013

Antioxidants & Redox Signaling

196

165

View full text Add to dashboard Cite

show abstract

“…TRAIL, but not AD5-10, could induce significant activation of caspase-3 and cleavage of c-FLIP L in H460 cells (18). It is notable that AD5-10-induced cell death is different from that induced by TRAIL in terms of ROS aggregation and JNK activation (19). DR5 can signal various downstream messages when activated by different ligands.…”

mentioning

confidence: 99%

Targeting a Novel N-terminal Epitope of Death Receptor 5 Triggers Tumor Cell Death

Zhang

Zheng

Shi

et al. 2010

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Tumor necrosis factor-related apoptosis-inducing ligand receptors death receptor (DR) 4 and DR5 are potential targets for antibody-based cancer therapy. Activation of the proapoptotic DR5 in various cancer cells triggers the extrinsic and/or intrinsic pathway of apoptosis. It has been shown that there are several functional domains in the DR5 extracellular domain. The cysteine-rich domains of DR5 have a conservative role in tumor necrosis factor-related apoptosis-inducing ligand-DR5-mediated apoptosis, and the pre-ligand assembly domain within the N1-cap contributes to the ligand-independent formation of receptor complexes. However, the role of the N-terminal region (NTR) preceding the N1-cap of DR5 remains unclear. In this study, we demonstrate that NTR could mediate DR5 activation that transmits an apoptotic signal when bound to a specific agonistic monoclonal antibody. A novel epitope in the NTR of DR5 was identified by peptide array. Antibodies against the antigenic determinant showed high affinities for DR5 and triggered caspase activation in a time-dependent manner, suggesting the NTR of DR5 might function as a potential death-inducing region. Moreover, permutation analysis showed that Leu 6 was pivotal for the interaction of DR5 and the agonistic antibody. Synthetic wild-type epitopes eliminated the cytotoxicity of all three agonistic monoclonal antibodies, AD5-10, Adie-1, and Adie-2. These results indicate that the NTR of DR5 could be a potential target site for the development of new strategies for cancer immunotherapy. Also, our findings expand the current knowledge about DR5 extracellular functional domains and provide insights into the mechanism of DR5-mediated cell death.Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) 4 is a attractive candidate for cancer therapy because it can triggers the extrinsic and/or intrinsic pathway of apoptosis in a variety of tumor cells by engaging the death receptors DR4 and DR5, while sparing most normal cells (1-5). However, decoy receptors (DcR1, DcR2, and OPG) compete for binding of TRAIL and protect cells from TRAIL-mediated cell death (6 -10). In this case, agonistic monoclonal antibodies (mAbs) against DR4/5 have shown encouraging results and potential in the therapeutic aspect of diseases.There are a number of agonistic mAbs against human DR4 or DR5 reported in the literature (11-13), and they have demonstrated more specific cell death-inducing activities. Most of these mAbs either need a cross-linker to ensure effective killing of tumor cells (14, 15) or compete with TRAIL for binding with DR5 (12, 16), mimicking the apoptosis-inducing mechanism of TRAIL. Guo et al. (17) from our laboratory reported that a novel anti-human DR5 monoclonal antibody AD5-10 induces the apoptosis of various carcinoma cell lines without cross-linking in vitro and exhibits strong tumoricidal activity in vivo. Furthermore, AD5-10 does not induce cell death of normal human hepatocytes or primary peripheral blood lymphocytes, and injection of AD5-10 into mice causes n...

show abstract

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

Cited by 17 publications

References 46 publications

Death Receptors 4 and 5 Activate Nox1 NADPH Oxidase through Riboflavin Kinase to Induce Reactive Oxygen Species-mediated Apoptotic Cell Death

Death Receptors 4 and 5 Activate Nox1 NADPH Oxidase through Riboflavin Kinase to Induce Reactive Oxygen Species-mediated Apoptotic Cell Death

Redox Regulation of T-Cell Function: From Molecular Mechanisms to Significance in Human Health and Disease

Targeting a Novel N-terminal Epitope of Death Receptor 5 Triggers Tumor Cell Death

Contact Info

Product

Resources

About