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Volume 272, Number 38, Issue of September 19, 1997 pp. 23481-23484
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

COMMUNICATION:
Protein Kinase CII Activation by 1--D-Arabinofuranosylcytosine Is Antagonistic to Stimulation of Apoptosis and Bcl-2 Down-regulation

(Received for publication, June 11, 1997, and in revised form, July 22, 1997)

From the Department of Biochemistry, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, North Carolina 27157-1016

1--D-Arabinofuranosylcytosine (ara-C) stimulates the formation of both diglyceride and ceramide in the acute myelogenous leukemia cell line HL-60 (Strum, J. C., Small, G. W., Pauig, S. B., and Daniel, L. W. (1994) J. Biol. Chem 269, 15493-15497). ara-C also causes apoptosis in HL-60 cells which can be mimicked by exogenous ceramide. However, the signaling role for ara-C-induced diacylglycerol (DAG) is not defined. We found that Bcl-2 levels were increased by treatment of HL-60 cells with exogenous DAG or 12-O-tetradecanoylphorbol-13-acetate (TPA). In contrast, exogenous ceramide treatment caused a decrease in cellular Bcl-2 levels. Thus, ara-C stimulates the synthesis of two second messengers with opposing effects on Bcl-2. Since the effects of ara-C-induced DAG could be due to protein kinase C (PKC) activation, we determined the effects of ara-C on PKC isozymes. ara-C caused an increase in membrane-bound PKCII (but not PKC or PKC). ara-C or TPA-induced translocation of PKCII was inhibited by 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine (ET-18-OCH₃), and ara-C-induced apoptosis was stimulated by pretreatment of the cells with ET-18-OCH₃. ET-18-OCH₃ also inhibited stimulation of Bcl-2 by TPA and enhanced the decrease in Bcl-2 observed in ara-C-treated cells. These data indicate that ara-C-induced apoptosis is limited by ara-C-stimulated PKCII through effects on Bcl-2. To further determine the role of PKC, we used antisense oligonucleotides directed toward PKCII. The antisense, but not the sense, oligonucleotide inhibited PKCII activation and enhanced ara-C-induced apoptosis. These data demonstrate that the stimulation of apoptosis by ara-C is self-limiting and can be enhanced by inhibition of PKC.

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