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 kinase (ERK), c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK), and p38 mitogen-activated protein kinase (MAPK). 2'-Amino-3'-methoxyflavone (PD098059) and 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole (SB203580) were used to inhibit the activity of ERK and p38, respectively. SEK-AL, a dominant-negative mutant of SEK1, was transfected into HL-60 cells (HL-60/SEK-AL) to assess the role of JNK/SAPK activity in apoptosis. PD098059 (25 microM) inhibited ara-C-induced caspase-3-like activity but was ineffective in altering ara-C-mediated apoptotic DNA fragmentation and clonogenicity. On the other hand, SB203580 (20 microM) inhibited ara-C-induced caspase-3-like activity, apoptotic DNA fragmentation, and clonogenicity. The inhibition of JNK1 activation in HL-60/SEK-AL cells did not block ara-C-induced apoptotic DNA fragmentation. These results suggest that ara-C-induced apoptotic DNA fragmentation and loss of clonogenicity occur through a p38-dependent pathway.
Stadheim
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TA
Comprehensive Cancer Center of Wake Forest University School of Medicine, Department of Physiology and Pharmacology, Winston-Salem, NC 27157, USA.
Saluta
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GR
Kucera
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GL
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D003561:Cytarabine / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018922:HL-60 Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases
D004791:Enzyme Inhibitors; D003561:Cytarabine; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases