Methylglyoxal induces apoptosis in Jurkat leukemia T cells by activating c-Jun N-Terminal kinase

Abstract

Methylglyoxal (MG) is a physiological metabolite, but it is known to be toxic, inducing stress in cells and causing apoptosis. This study examines molecular mechanisms in the MG-induced signal transduction leading to apoptosis, focusing particularly on the role of JNK activation. We first confirmed that MG caused apoptosis in Jurkat cells and that it was cell type dependent because it failed to induce apoptosis in MOLT-4, HeLa, or COS-7 cells. A caspase inhibitor, Z-DEVD-fmk, completely blocked MG-induced poly(ADP-ribose)polymerase (PARP) cleavage and apoptosis, showing the critical role of caspase activation. Inhibition of JNK activity by a JNK inhibitor, curcumin, remarkably reduced MG-induced caspase-3 activation, PARP cleavage, and apoptosis. Stable expression of the dominant negative mutant of JNK also protected cells against apoptosis notably, although not completely. Correspondingly, loss of the mitochondrial membrane potential induced by MG was decreased by the dominant negative JNK. These results confirmed a crucial role of JNK working upstream of caspases, as well as an involvement of JNK in affecting the mitochondrial membrane potential.

Glyoxalase I Is Critical for Human Retinal Capillary Pericyte Survival under Hyperglycemic Conditions

“…Kim et al (22) report that MGO-mediated apoptosis in retinal pericytes may occur via an oxidative stress mechanism involving NF-B (22). Du et al (47,48) likewise suggest a role for oxidative stress generated by incubation of Jurkat cells with MGO, which then triggers c-Jun NH 2 -terminal kinase activation and subsequent apoptosis. Inactivation of GAPDH can elevate levels of MGO because MGO is formed from the substrate of GAPDH, glyceraldehyde 3-phosphate (49).…”

Analysis of Methylglyoxal Metabolism in CHO Cells Grown in Culture

“…Increased endogenous MG directly initiates cell death signaling cascades in some instances, whilst in others it occurs as a consequence of cell death activation. Specific pathway activation is cell-line dependent and results in either necrosis-or apoptosis-like end states (Du et al 2000;Sakamoto et al 2000;Godbout et al 2001;Vander Jagt et al 2001).…”

Phorbol 12-Myristate 13-Acetate Protects Jurkat Cells from Methylglyoxal-Induced Apoptosis by Preventing c-Jun N-Terminal Kinase-Mediated Leakage of Cytochromecin an Extracellular Signal-Regulated Kinase-Dependent Manner

“…Apoptosis was judged by DNA fragmentation as described previously (Du et al, 2000). Stimulated cells were harvested and resuspended in propidium iodide (PI) buffer (0.1% Triton X-100, 0.1% trisodium citrate, and 50 g/ml PI).…”

“…We showed previously that Jurkat T lymphocytes exposed to MG rapidly undergo apoptosis in association with mitochondrial dysfunction and caspase activation (Du et al, 2000). Although the mechanisms by which MG triggers apoptotic events are not fully understood, our previous studies have suggested that intense activation of the JNK pathway triggered by MG contributes to mitochondrial dysfunction and subsequent cell death (Du et al, 2000.…”

“…Although the mechanisms by which MG triggers apoptotic events are not fully understood, our previous studies have suggested that intense activation of the JNK pathway triggered by MG contributes to mitochondrial dysfunction and subsequent cell death (Du et al, 2000. The JNK pathway is activated by diverse apoptosis-inducing stresses, including UV irradiation and exposure to hydrogen peroxide, heat, and osmotic shock.…”