Role of c-Jun N-terminal kinase/p38 stress signaling in 1-beta-D-arabinofuranosylcytosine-induced apoptosis

1-beta-D-Arabinofuranosylcytosine (ara-C) induced apoptosis in HL-60 cells, which was preceded by the activation of extracellular signal-regulated kin ase (ERK), c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAP K), and p38 mitogen-activated protein kinase (MAPK). 2'-Amino-3'-methoxyfla vone (PD098059) and 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyri dyl)1H-imidazole (SB203580) were used to inhibit the activity of ERK and p3 8, respectively. SEK-AL, a dominant-negative mutant of SEK1, was transfecte d into HL-60 cells (HL-60/SEK-AL) to assess the role of JNK/SAPK activity i n apoptosis. PD098059 (25 mu M) inhibited ara-C-induced caspase-3-like acti vity but was ineffective in altering ara-C-mediated apoptotic DNA fragmenta tion and clonogenicity. On the other hand, SB203580 (20 mu M) inhibited ara -C-induced caspase-3-like activity, apoptotic DNA fragmentation, and clonog enicity. The inhibition of JNK1 activation in HL-60/SEK-AL cells did not bl ock ara-C-induced apoptotic DNA fragmentation. These results suggest that a ra-C-induced apoptotic DNA fragmentation and loss of clonogenicity occur th rough a p38-dependent pathway. BIOCHEM PHARMACOL 59;4:407-418, 2000. (C) 20 00 Elsevier Science Inc.