JNK activation is a mediator of arsenic trioxide-induced apoptosis in acute promyelocytic leukemia cells.
Arsenic trioxide induces c-jun N-terminal kinase (JNK) activation and apoptosis in acute promyelocytic leukemia (APL), where it has major clinical activity, but whether JNK is necessary to induce apoptosis is unknown. To clarify this necessity, we established 2 arsenic trioxide (As(2)O(3))-resistant subclones of the APL cell line, NB4. Both resistant lines showed little activation of JNK1 following treatment with As(2)O(3), even at doses sufficient to elicit robust activation in NB4 cells. One mechanism of resistance in these cells is up-regulated glutathione (GSH) content, and GSH depletion by l-buthionine-[S,R]-sulfoximine (BSO) restores JNK activation and As(2)O(3) sensitivity. This correlation between JNK activation and apoptosis led us to test whether inhibition of JNK would protect cells from As(2)O(3)-induced apoptosis. SEK1(-/-) mouse embryo fibroblasts (MEFs) showed diminished JNK activation following As(2)O(3) treatment and were protected from As(2)O(3)-induced but not doxorubicin-induced apoptosis. Furthermore, treatment of arsenic trioxide-sensitive APL cells with the JNK inhibitor, dicumarol, significantly increased growth and survival in response to As(2)O(3) but did not protect cells from doxorubicin. Together, these data support an essential role for JNK signaling in the induction of growth inhibition and apoptosis by As(2)O(3) and suggest that activating JNK may provide a therapeutic advantage in the treatment of cancers that do not respond to arsenic alone.
Davison
Kelly
K
Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, McGill University, Montréal, Québec, Canada.
Mann
Koren K
KK
Waxman
Samuel
S
Miller
Wilson H
WH
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002999:Clone Cells / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation / Q000187:drug effects; D005978:Glutathione / Q000494:pharmacology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D015473:Leukemia, Promyelocytic, Acute / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism* / Q000502:physiology; D010087:Oxides / Q000494:pharmacology*; D036122:Receptor, EphA4 / Q000235:genetics
D001152:Arsenicals; D010087:Oxides; D036122:Receptor, EphA4; D048031:JNK Mitogen-Activated Protein Kinases; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D005978:Glutathione; D000077237:Arsenic Trioxide