Effects of inducers of differentiation on protein kinase C and CMP-N-acetylneuraminic acid:lactosylceramide sialyltransferase activities of HL-60 leukemia cells.

Abstract

Exposure of HL-60 leukemia cells to either 12-O-tetradecanoylphorbol-13-acetate (TPA), dimethylsulfoxide (DMSO), exogenous gangliosides GM3, GM1, or bovine brain ganglioside mixture (BBG) resulted in a marked inhibition of the growth of cells. The order of the inhibitory potency was TPA greater than GM3 greater than DMSO greater than BBG greater than GM1. In contrast, sulfatides were without effect on cellular replication. Treatment of HL-60 cells with TPA or GM3 induced differentiation along the monocyte/macrophage lineage, while treatment with DMSO induced maturation along the granulocytic pathway. These effects were accompanied by more than a twofold increase in protein kinase C (PKC) activity. In contrast, treatment with GM1, BBG, or sulfatides caused only a relatively small increase in PKC activity. The activity of CMP-N-acetylneuraminic acid:lactosylceramide sialyltransferase (ST1), a key enzyme for membrane gangliosides synthesis, in HL-60 cells was also influenced by the exposure to TPA, GM3, DMSO, GM1, or sulfatides. The inducers of differentiation, TPA and DMSO, caused an increase in ST1 activity, whereas GM3, which also induced cellular differentiation, inhibited ST1 activity, perhaps through the action of end-product inhibition. The non-inducers of differentiation, GM1 and sulfatides, also increased the activity of ST1, but to a much lesser extent. The findings suggest that the direct or indirect modulation of PKC activity by some of these agents may be involved, at least in part, in the regulation of cellular growth and differentiation. Furthermore, it is conceivable that differences in PKC activity may be responsible for the changes in ST1 activity associated with cell differentiation and proliferation.