Competitive inhibition of choline phosphotransferase by geranylgeraniol and farnesol inhibits phosphatidylcholine synthesis and induces apoptosis in human lung adenocarcinoma A549 cells.
We have previously shown that, among various isoprenoids, farnesol and geranylgeraniol specifically induced actin fiber disorganization, growth inhibition, and apoptosis in human lung adenocarcinoma A549 cells (Miquel, K., Pradines, A., and Favre, G. (1996) Biochem. Biophys. Res. Commun. 225, 869-876). Here we demonstrate that isoprenoid-induced apoptosis was preceded by an arrest in G0/G1 phase. The isoprenoid effects were independent of protein prenylation and of mitogen-activated protein kinase activity. Moreover, geranylgeraniol and farnesol induced a rapid inhibition of phosphatidylcholine biosynthesis at the last step of the CDP-choline pathway controlled by choline phosphotransferase and not at the level of CTP:phosphocholine cytidylyltransferase, the key enzyme of the pathway. Inhibition of choline phosphotransferase was confirmed by in vitro assays on microsomal fractions, which clearly showed that the isoprenoids acted by competitive inhibition with the diacylglycerol binding. Exogenous phosphatidylcholine addition prevented all the biological effects of the isoprenoids, including actin fiber disorganization and apoptosis, suggesting that inhibition of phosphatidylcholine biosynthesis might be the primary event of the isoprenoid action. These data demonstrate the molecular mechanism of geranylgeraniol and farnesol effects and suggest that the mevalonate pathway, leading notably to prenylated proteins, might be linked to the control of cell proliferation through the regulation of phosphatidylcholine biosynthesis.
Miquel
K
K
Laboratoire d'Oncologie Cellulaire et Moléculaire, EA 2048, Faculté des Sciences Pharmaceutiques et Centre de Lutte Contre le Cancer Claudius Regaud, 31052 Toulouse cedex, France.
Pradines
A
A
Tercé
F
F
Selmi
S
S
Favre
G
G
D000199:Actins / Q000032:analysis; D017209:Apoptosis / Q000187:drug effects*; D001667:Binding, Competitive; D002455:Cell Division / Q000502:physiology; D002794:Choline / Q000378:metabolism; D019916:Choline-Phosphate Cytidylyltransferase / Q000378:metabolism; D003566:Cytidine Diphosphate Choline / Q000378:metabolism; D003599:Cytoskeleton / Q000187:drug effects; D002798:Diacylglycerol Cholinephosphotransferase / Q000037:antagonists & inhibitors*; D004075:Diglycerides / Q000378:metabolism; D004224:Diterpenes / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005204:Farnesol / Q000494:pharmacology*; D006801:Humans; D007399:Interphase / Q000502:physiology; D008856:Microscopy, Fluorescence; D008861:Microsomes / Q000201:enzymology; D010713:Phosphatidylcholines / Q000096:biosynthesis* / Q000494:pharmacology; D017368:Protein Prenylation / Q000187:drug effects; D014407:Tumor Cells, Cultured
D000199:Actins; D004075:Diglycerides; D004224:Diterpenes; D004791:Enzyme Inhibitors; D010713:Phosphatidylcholines; D005204:Farnesol; D003566:Cytidine Diphosphate Choline; C017338:geranylgeraniol; D019916:Choline-Phosphate Cytidylyltransferase; D002798:Diacylglycerol Cholinephosphotransferase; D002794:Choline