Inhibition of sterol and phospholipid synthesis in HL-60 promyelocytic leukemia cells by inducers of myeloid differentiation.
Myeloid differentiation is induced in HL-60 promyelocytic leukemia cells by dimethyl sulfoxide, retinoic acid, hypoxanthine, and a number of other chemical agents. We questioned whether the induction process was associated with changes in lipid synthesis. With [14C]acetate, a precursor for all cell lipids, a decrease in sterol and phospholipid synthesis (but not triglyceride synthesis) was observed within the first 5 hr after exposure to inducer, a time prior to inhibition of DNA synthesis or cessation of cell growth. Similarly, the membrane fraction of HL-60 cells exhibited decreased incorporation of newly synthesized lipid. Synthesis of phosphatidylcholine from choline as well as from the transmethylation of membrane phosphatidylethanolamine was also inhibited by myeloid inducers. In contrast, neither sterol nor phospholipid degradation was stimulated under these conditions. Both cholesterol and lanosterol were synthesized by growing HL-60 cells, but cholesterol esters were not. Synthesis of sterols was subject to feedback inhibition by cholesterol in the medium, but such feedback inhibition did not affect differentiation in the presence of myeloid inducers and did not alter the effect of myeloid inducers on phospholipid synthesis. Removal of dimethyl sulfoxide at 16 hr permitted a return to normal lipid synthesis and prevented differentiation, whereas removal of dimethyl sulfoxide at 40 hr was followed by continued inhibition of lipid synthesis and progressive differentiation. These studies demonstrate that the induction of myeloid differentiation is associated with an early inhibition of the synthesis of those lipids which are normally a part of cell membranes.