Competitive Inhibition of Choline Phosphotransferase by Geranylgeraniol and Farnesol Inhibits Phosphatidylcholine Synthesis and Induces Apoptosis in Human Lung Adenocarcinoma A549 Cells

Abstract

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 isoprenoidinduced apoptosis was preceded by an arrest in G 0 /G 1 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.

A third-generation bisphosphonate, minodronic acid (YM529), successfully prevented the growth of bladder cancer in vitro and in vivo

“…However, because cytotoxicity of GGOH and FOH hamper these experiments, we could not determine whether YM529 inhibits geranylgeranylation and/or farnesylation in bladder cancer cells (data not shown). These results are consistent with the previous studies that GGOH and FOH induce apoptosis for the several kinds of cells (Miquel et al, 1998, Wright et al, 2001.…”

Vitamin E analogues as inducers of apoptosis: structure–function relation

“…One possibility is that g-T3H acts via inhibition of prenylation (Theriault et al, 2002). Indeed, other compounds, which block prenylation, have been shown to be strong apoptogens (Miquel et al, 1998;Rioja et al, 2000). It is tempting to hypothesise that compounds like g-T3H or g-T2H may prevent carcinogenesis by suppressing prenylation of crucial oncogenes, such as Ras (Adjei 2001), in which case these agents would have prophylactic effects.…”

Effect of farnesol on mevalonate pathway of Staphylococcus aureus

“…[7][8][9] Their HMG-CoA reductases came from Chinese hamster ovary cell, Met-18b-2 cell and HL60 etc. They are class I HMG-CoA reductase.…”