Inhibition of phosphatidylcholine biosynthesis following induction of apoptosis in HL-60 cells.
Induction of apoptosis in HL-60 cells, using a variety of cytotoxic drugs, resulted, in all cases, in inhibition of CDP-choline:1, 2-diacylglycerol choline phosphotransferase, leading to an accumulation of its substrate, CDP-choline, and inhibition of phosphatidylcholine biosynthesis. Incubation of the cells with phosphatidylcholine reduced the number displaying an apoptotic morphology following drug treatment, and this was inversely related to the degree to which the drugs inhibited phosphatidylcholine biosynthesis. Inhibition of choline phosphotransferase by two of the drugs, farnesol and chelerythrine, was shown to be due to direct inhibition of the enzyme, while inhibition by the other drugs, etoposide and camptothecin, could be explained by the intracellular acidification that followed induction of apoptosis.
Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Old Addenbrookes Site, Cambridge CB2 1GA, United Kingdom.
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Anthony
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Zhao
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Brindle
D000470:Alkaloids; D017209:Apoptosis / Q000187:drug effects*; D053119:Benzophenanthridines; D002166:Camptothecin / Q000494:pharmacology; D002794:Choline / Q000378:metabolism; D003566:Cytidine Diphosphate Choline / Q000378:metabolism; D002798:Diacylglycerol Cholinephosphotransferase / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D005204:Farnesol / Q000494:pharmacology; D005434:Flow Cytometry; D018922:HL-60 Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D010617:Phenanthridines / Q000494:pharmacology; D010713:Phosphatidylcholines / Q000096:biosynthesis* / Q000494:pharmacology; D010767:Phosphorylcholine / Q000378:metabolism
D000470:Alkaloids; D053119:Benzophenanthridines; D004791:Enzyme Inhibitors; D010617:Phenanthridines; D010713:Phosphatidylcholines; D010767:Phosphorylcholine; D005204:Farnesol; D003566:Cytidine Diphosphate Choline; D005047:Etoposide; C016299:chelerythrine; D002798:Diacylglycerol Cholinephosphotransferase; D002794:Choline; D002166:Camptothecin