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J Biol Chem, Vol. 274, Issue 33, 23526-23534, August 13, 1999

Involvement of Protein Kinase C- and Ceramide in Tumor Necrosis Factor--induced but Not Fas-induced Apoptosis of Human Myeloid Leukemia Cells

From the Gene Expression and Function Group, Biochip Technology Center, Argonne National Laboratory, Argonne, Illinois 60439-4833

The role of protein kinase C- (PKC-) in apoptosis induced by tumor necrosis factor (TNF)- and anti-Fas monoclonal antibody (mAb) in the human myeloid HL-60 leukemia cell line was studied by using its variant HL-525, which is deficient in PKC-. In contrast to the parental HL-60 cells, HL-525 is resistant to TNF--induced apoptosis but sensitive to anti-Fas mAb-induced apoptosis. Both cell types expressed similar levels of the TNF-receptor I, whereas the Fas receptor was detected only in HL-525 cells. Transfecting the HL-525 cells with an expression vector containing PKC- reestablished their susceptibility to TNF--induced apoptosis. The apoptotic effect of TNF- in HL-60 and the transfectants was abrogated by fumonisin, an inhibitor of ceramide generation, and by the peptide Ac-YVAD-BoMK, an inhibitor of caspase-1 and -4. Supplementing HL-525 cells with exogenous ceramides bypassed the PKC- deficiency and induced apoptosis, which was also restrained by the caspase-1 and -4 inhibitor. The apoptotic effect of anti-Fas mAb in HL-525 cells was abrogated by the antioxidants N-acetylcysteine and glutathione and by the peptide z-DEVD-FMK, an inhibitor of caspase-3 and -7. We suggest that TNF--induced apoptosis involves PKC- and then ceramide and, in turn, caspase-1 and/or -4, whereas anti-Fas mAb-induced apoptosis utilizes reactive oxygen intermediates and, in turn, caspase-3 and/or -7.

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