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Vol. 52, Issue 6, 935-947, 1997
Departments of
Medicine (W.D.J., A.J.F., S.G.),
Medicinal Chemistry
(F.A.F.),
Radiation Oncology (K.L.A., P.D.),
Microbiology/Immunology
(C.R.J., S.E.B., S.G.), and
Pharmacology/Toxicology (P.D., S.G.),
Medical College of Virginia, Richmond, Virginia 23298, and
Biomarkers
and Prevention Research Branch (E.S., M.J.B.), National Cancer
Institute, National Institutes of Health, Bethesda, Maryland 20850
We characterized participation of the stress-activated
protein kinase (SAPK) cascade in the lethal actions of the cytotoxic lipid messengers ceramide and sphingosine in U937 human monoblastic leukemia cells. Acute exposure of U937 cells to either lipid resulted in loss of proliferative capacity, degradation of genomic DNA, and
manifestation of apoptotic cytoarchitecture. Ceramide robustly stimulated p46-JNK1/p54-JNK2 activity and increased expression of
c-jun mRNA and c-Jun protein; in contrast, sphingosine
moderately stimulated p46-JNK1/p54-JNK2 and failed to modify
c-jun/c-Jun expression. Dominant-negative blockade of
normal c-Jun activity by transfection with the TAM-67 c-Jun
NH2-terminal deletion mutant abolished the lethal actions
of ceramide but was without effect on those of sphingosine, indicating
that ceramide-related apoptosis is directly dependent on activation of
c-Jun, whereas sphingosine-induced cell death proceeds via an unrelated
downstream mechanism. Characterization of the mitogen-activated protein
kinase (MAPK) cascade in these responses revealed a further functional
disparity between the two lipids: basal p42-ERK1/p44-ERK2 activity was
gradually reduced by ceramide but immediately and completely
suppressed by sphingosine. Moreover, blockade of the MAPK cascade by
the aminomethoxyflavone MEK1 inhibitor PD-98059 unexpectedly activated
p46-JNK1/p54-JNK2 and induced apoptosis in a manner qualitatively
resembling that of sphingosine. Both lipids sharply increased p38-RK
activity; selective pharmacological inhibition of p38-RK by the
pyridinyl imidazole SB-203580 failed to mitigate the cytotoxicity
associated with either ceramide or sphingosine, suggesting that p38-RK
is not essential for lipid-induced apoptosis. These findings
demonstrate that reciprocal alterations in the SAPK and MAPK cascades
are associated with the apoptotic influence of either lipid inasmuch as
(i) ceramide-mediated lethality is primarily associated with strong
stimulation of SAPK and weak inhibition of MAPK, whereas (ii)
sphingosine-mediated lethality is primarily associated with weak
stimulation of SAPK and strong inhibition of MAPK. We therefore propose
that leukemic cell survival depends on the maintenance of an imbalance
of the outputs from the MAPK and SAPK systems such that the dominant
basal influence of the MAPK cascade allows sustained proliferation,
whereas acute redirection of this balance toward the SAPK cascade
initiates apoptotic cell death.
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