Uncoupling Farnesol-induced Apoptosis from Its Inhibition of Phosphatidylcholine Synthesis

Abstract

Genetic inactivation of the synthesis of phosphatidylcholine, the most abundant membrane lipid in eukaryotic cells, induces apoptosis. Administration of farnesol, a catabolite within the isoprenoid/cholesterol pathway, also induces apoptosis. The mechanism by which farnesol induces apoptosis is currently believed to be by direct competitive inhibition with diacylglycerol for cholinephosphotransferase, the final step in the phosphatidylcholine biosynthetic pathway. Our recent isolation of the first mammalian cholinephosphotransferase cDNA has enabled us to more precisely assess how farnesol affects phosphatidylcholine synthesis and the induction of apoptosis. Induced over-expression of cholinephosphotransferase in Chinese hamster ovary cells prevented the block in phosphatidylcholine biosynthesis associated with exposure to farnesol. However, induced over-expression of cholinephosphotransferase was not sufficient for the prevention of farnesol-induced apoptosis. In addition, exogenous administration of diacylglycerol prevented farnesol-induced apoptosis but did not relieve the farnesol-induced block in phosphatidylcholine synthesis. We also developed an in vitro lipid mixed micelle cholinephosphotransferase enzyme assay, as opposed to the delivery of the diacylglycerol substrate in a detergent emulsion, and demonstrated that there was no direct inhibition of cholinephosphotransferase by farnesol or its phosphorylated metabolites. The execution of apoptosis by farnesol appears to be a separate and distinct event from farnesol-induced inhibition of phosphatidylcholine biosynthesis and instead likely occurs through a diacylglycerol-mediated process that is downstream of phosphatidylcholine synthesis.

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.…”

Phospholipid Biosynthesis Program Underlying Membrane Expansion during B-lymphocyte Differentiation

“…Thus, CPT is not just a marker of ER membrane expansion but may also be a critical factor in the phospholipid response to LPS. However, increased CPT expression alone is not sufficient to drive PtdCho synthesis in other systems (29). The similarity in the gene expression patterns of Lipin1 and CPT suggests that they may be regulated coordinately.…”

“…Finally, in the last step of PtdCho synthesis, the CPT uses both CDP-choline and DAG as substrates. Thus, in addition to the supply of CDP-choline, the supply of DAG can be a limiting factor in membrane PtdCho biosynthesis (27)(28)(29)(30).…”

Pharmacometabolomics of docetaxel-treated human MCF7 breast cancer cells provides evidence of varying cellular responses at high and low doses

“…DTX at low concentration (10 nM) was shown to activate DGK, a lipid kinase that catalyzes DAG conversion into PA. DTX triggers a metabolic cascade consisting in phospholipase D-mediated PtC hydrolysis, PA release, phosphatidic acid phosphatase-dependent DAG production, and DGK stimulation leading to DAG conversion back to PA [18]. Finally, another mechanism for CPT blockade may be proposed, a competition between DAG and cholesterol precursors, a mechanism which was shown to provoke CDPC accumulation and inhibit PtC biosynthesis [43]. At clinical dose of DTX, PtC was found to be a positive biomarker of membrane integrity.…”