c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) is required for mitoxantrone- and anisomycin-induced apoptosis in HL-60 cells.
Programmed cell death, or apoptosis, has emerged as a common mechanism by which cells respond to chemotherapeutic drugs. However, the signaling mechanisms that mediate drug-induced apoptosis are still widely unknown. Mitogen-activated protein kinase (MAPK) signaling cascades trigger stimulus-specific responses in cells with ERK being associated with proliferation and differentiation, and JNK/SAPK and p38 mediating stress and apoptotic responses. Here, we found that mitoxantrone and anisomycin stimulated a dose- and time-dependent induction of JNK/SAPK activity, and to a lesser extent p38 activity, that preceded the appearance of apoptosis as measured by internucleosomal DNA fragmentation. These compounds did not induce ERK activity. We further demonstrated that p38 activity was not involved in the induction of apoptosis since the use of the p38 inhibitor, SB203580, did not prevent drug-induced apoptotic DNA fragmentation. Additionally, direct inhibition of JNK/SAPK signaling through the use of dominant-negative MKK4/SEK1 (SEK-AL) inhibited mitoxantrone- and anisomycin-induced apoptosis. These results suggest that mitoxantrone- and anisomycin-induced apoptosis is dependent on JNK/SAPK, but not p38, activity.
Stadheim
Terrance A
TA
Department of Physiology and Pharmacology, Comprehensive Cancer Center, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.
Kucera
Gregory L
GL
D000841:Anisomycin / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D004273:DNA, Neoplasm / Q000032:analysis; D005419:Flavonoids / Q000494:pharmacology; D018922:HL-60 Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases; D007951:Leukemia, Myeloid / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008942:Mitoxantrone / Q000494:pharmacology*; D011233:Precipitin Tests; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D005419:Flavonoids; D007093:Imidazoles; D011500:Protein Synthesis Inhibitors; D011725:Pyridines; D000841:Anisomycin; D008942:Mitoxantrone; D048031:JNK Mitogen-Activated Protein Kinases; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one