Methylglyoxal induces apoptosis in Jurkat leukemia T cells by activating c-jun N-terminal kinase

Methylglyoxal (MG) is a physiological metabolite, but it is known to be tox ic, inducing stress in cells and causing apoptosis. This study examines mol ecular mechanisms in the MG-induced signal transduction leading to apoptosi s, focusing particularly on the role of JNK activation. We first confirmed that MC caused apoptosis in jurkat cells and that it was cell type dependen t 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-ribos e)polymerase (PARP) cleavage and apoptosis, showing the critical role of ca spase activation. Inhibition of JNK activity by a JNK inhibitor, curcumin, remarkably reduced MG-induced caspase-3 activation, PARP cleavage, and apop tosis. Stable expression of the dominant negative mutant of JNK also protec ted cells against apoptosis notably, although not completely. Corresponding ly, loss of the mitochondrial membrane potential induced by MC was decrease d by the dominant negative JNK. These results confirmed a crucial role of J NK working upstream of caspases, as well as an involvement of JNK in affect ing the mitochondrial membrane potential. (C) 2000 Wiley-Liss, Inc.