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Vol. 54, Issue 5, 844-856, November 1998
-D-Arabinofuranosylcytosine-Induced Apoptosis by
Interruption of Protein Kinase C Signaling
Departments of
Medicine (W.D.J., R.M.T., S.G.),
Pharmacology/Toxicology (R.M.T., P.D., S.G.), and
Radiation Oncology
(P.D.), Medical College of Virginia, Richmond, Virginia 23298, Dominion
Diagnostics, Richmond, Virginia 23231 (F.A.F.),
Department of Chemistry
and Biochemistry, Queens College of the City University of New York,
Flushing, New York 11367 (R.K.E., R.B.), and
Department of Medicine,
Memorial Sloan-Kettering Cancer Center, New York, New York 10021 (G.W.S.)
The stress-activated protein kinase (SAPK) and mitogen-activated
protein kinase (MAPK) cascades mediate cytotoxic and cytoprotective functions, respectively, in the regulation of leukemic cell survival. Involvement of these signaling systems in the cytotoxicity of 1-
-D-arabinofuranosylcytosine (ara-C) and modulation of
ara-C lethality by protein kinase C PKC inhibition/down-regulation was examined in HL-60 promyelocytic leukemia cells. Exposure to ara-C (10 µM) for 6 hr promoted extensive apoptotic DNA damage and
cell death, as well as activation of PKC. This response was accompanied by downstream activation of the SAPK and MAPK cascades. PKC-dependent MAPK activity seemed to limit ara-C action in that the toxicity of
ara-C was enhanced by pharmacological reductions of PKC, MAPK, or both.
Thus, ara-C action was (1) partially attenuated by diradylglycerols, which stimulated PKC and MAPK, but (2) dramatically amplified by
sphingoid bases, which inhibited PKC and MAPK. The cytotoxicity of
ara-C also was substantially increased by pharmacological reductions of
PKC, including down-regulation of PKC by chronic preexposure to the
macrocyclic lactone bryostatin 1 or inhibition of PKC by acute
coexposure to the dihydrosphingosine analog safingol. Significantly, both of these manipulations prevented activation of MAPK by ara-C. Moreover, acute disruption of the MAPK module by AMF, a selective inhibitor of MEK1, suppressed both basal and drug-stimulated MAPK activity and sharply increased the cytotoxicity of ara-C, suggesting the direct involvement of MAPK as a downstream antiapoptotic effector for PKC. None of these chemopotentiating agents enhanced ara-CTP formation. Ceramide-driven SAPK activity did not seem to mediate drug-induced apoptosis, given that (1) neutralization of endogenous tumor necrosis factor-
with monoclonal antibodies or soluble tumor
necrosis factor receptor substantially reduced ceramide generation and
SAPK activation by ara-C, whereas the induction of apoptosis was
unaffected; (2) pharmacological inhibition of sphingomyelinase by
3-O-methoxysphingomyelin reduced ceramide generation and SAPK
activation without limiting the drug's cytotoxicity; and (3)
potentiation of ara-C action by bryostatin 1 or safingol was not
associated with further stimulation of SAPK. These observations collectively suggest a primary role for decreased MAPK, rather than
increased SAPK, in the potentiation of ara-C cytotoxicity by
interference with PKC-dependent signaling.
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