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Research ArticleArticle

Evidence for Involvement of Mitogen-Activated Protein Kinase, Rather than Stress-Activated Protein Kinase, in Potentiation of 1-β-d-Arabinofuranosylcytosine-Induced Apoptosis by Interruption of Protein Kinase C Signaling

W. David Jarvis, Frank A. Fornari Jr., Robert M. Tombes, Ravi K. Erukulla, Robert Bittman, Gary K. Schwartz, Paul Dent and Steven Grant
Molecular Pharmacology November 1998, 54 (5) 844-856; DOI: https://doi.org/10.1124/mol.54.5.844
W. David Jarvis
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Frank A. Fornari Jr.
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Robert M. Tombes
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Ravi K. Erukulla
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Robert Bittman
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Gary K. Schwartz
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Paul Dent
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Steven Grant
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Abstract

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-β-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-α 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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Molecular Pharmacology: 54 (5)
Molecular Pharmacology
Vol. 54, Issue 5
1 Nov 1998
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Research ArticleArticle

Evidence for Involvement of Mitogen-Activated Protein Kinase, Rather than Stress-Activated Protein Kinase, in Potentiation of 1-β-d-Arabinofuranosylcytosine-Induced Apoptosis by Interruption of Protein Kinase C Signaling

W. David Jarvis, Frank A. Fornari, Robert M. Tombes, Ravi K. Erukulla, Robert Bittman, Gary K. Schwartz, Paul Dent and Steven Grant
Molecular Pharmacology November 1, 1998, 54 (5) 844-856; DOI: https://doi.org/10.1124/mol.54.5.844

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Research ArticleArticle

Evidence for Involvement of Mitogen-Activated Protein Kinase, Rather than Stress-Activated Protein Kinase, in Potentiation of 1-β-d-Arabinofuranosylcytosine-Induced Apoptosis by Interruption of Protein Kinase C Signaling

W. David Jarvis, Frank A. Fornari, Robert M. Tombes, Ravi K. Erukulla, Robert Bittman, Gary K. Schwartz, Paul Dent and Steven Grant
Molecular Pharmacology November 1, 1998, 54 (5) 844-856; DOI: https://doi.org/10.1124/mol.54.5.844
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