Inhibition of Phosphatidylcholine Biosynthesis following Induction of Apoptosis in HL-60 Cells

Anthony, Maria L.; Zhao, Ming; Brindle, Kevin M.

doi:10.1074/jbc.274.28.19686

Cited by 115 publications

(110 citation statements)

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“…This would lead to an increase in the other PtdCho substrate DAG, which could then be converted to TAG by the cells to prevent disruption of cellular metabolism (Exton, 1994). Others have reported an inhibition of PtdCho synthesis at the level of cytidine diphoshate-choline:1,2-diacylglycerol choline phosphotransferase (CPT) following intracellular acidification (Williams et al, 1998;Anthony et al, 1999). This could be the cause for the accumulation of TAGs in our cells.…”

Section: Discussionmentioning

confidence: 89%

Apoptosis is associated with triacylglycerol accumulation in Jurkat T-cells

et al. 2002

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Magnetic resonance spectroscopy is increasingly used as a non-invasive method to investigate apoptosis. Apoptosis was induced in Jurkat T-cells by Fas mAb. 1 H magnetic resonance spectra of live cells showed an increase in methylene signal as well as methylene/methyl ratio of fatty acid side chains at 5 and 24 h following induction of apoptosis. To explain this observation, 1 H magnetic resonance spectra of cell extracts were investigated. These demonstrated a 70.0+7.0%, 114.0+8.0% and 90.0+5.0% increase in the concentration of triacylglycerols following 3, 5 and 7 h of Fas mAb treatment (P50.05). Confocal microscopy images of cells stained with the lipophilic dye Nile Red demonstrated the presence of lipid droplets in the cell cytoplasm. Quantification of the stained lipids by flow cytometry showed a good correlation with the magnetic resonance results (P50.05 at 3, 5 and 7 h). 31 P magnetic resonance spectra showed a drop in phosphatidylcholine content of apoptosing cells, indicating that alteration in phosphatidylcholine metabolism could be the source of triacylglycerol accumulation during apoptosis. In summary, apoptosis is associated with an early accumulation of mobile triacylglycerols mostly in the form of cytoplasmic lipid droplets. This is reflected in an increase in the methylene/methyl ratio which could be detected by magnetic resonance spectroscopy.

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Section: Discussionmentioning

confidence: 89%

Apoptosis is associated with triacylglycerol accumulation in Jurkat T-cells

et al. 2002

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“…19 It is interesting to note that apomine exerts antitumor activity in vitro 16,20 and in the 5T2MM mouse myeloma model 21 through mechanisms distinct from the down-regulation of HMG-CoA reductase, most likely involving inhibition of the phosphatidylcholine synthesis pathway, 18 again mimicking the actions of farnesol. [22][23][24] In a phase 1 study of apomine in patients with epithelial ovarian cancer, at the initial dose level (125 mg/m 2 daily), the plasma concentration on day 14 of the treatment cycle was 16.4 mg/mL (29.1 mM), and the time to reach it was 3.1 AE 2.3 hours. Its apparent terminal elimination half-life from 24 to 192 hours was 156.2 AE 42.9 hours.…”

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confidence: 99%

Synergistic inhibitory effect of apomine and lovastatin on osteosarcoma cell growth

Moriceau

Roelofs

Brion

et al. 2011

Cancer

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BACKGROUND: Osteosarcoma is the most frequent malignant primary bone tumor that occurs mainly in the young, with an incidence peak observed at age 18 years. Both apomine and lovastatin have antitumor activity in a variety of cancer cell lines. Apomine, a 1,1-bisphosphonate-ester, increases the rate of degradation of 3-hydroxy-3 methylglutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in the mevalonate pathway, whereas lovastatin competitively inhibits HMG-CoA reductase enzyme activity, thereby preventing protein prenylation and cholesterol synthesis. METHODS: The authors of this report investigated the effect of combined treatment with apomine and lovastatin in vitro on human and murine osteosarcoma cell lines and in vivo using a murine syngeneic model of osteosarcoma. Apomine and lovastatin synergistically decreased viability and induced apoptosis in both murine and human osteosarcoma cell lines. RESULTS: Combined apomine and lovastatin strongly decreased HMG-CoA reductase enzyme levels compared with lovastatin treatment alone. Consequently, the accumulation of unprenylated ras-related protein 1A induced by lovastatin was enhanced in the presence of apomine. All synergistic effects on cell viability, apoptosis, and protein prenylation were overcome by the addition of mevalonate or geranylgeraniol, 2 mevalonate pathway intermediates downstream from the target enzyme, HMG-CoA reductase. This confirmed that the mechanism of synergy in osteosarcoma cells is through augmented inhibition of HMG-CoA reductase. Finally, treatment of POS-1 osteosarcoma-bearing mice with a combination of apomine and lovastatin significantly reduced tumor progression in these mice compared with single treatments, which had no effect at the doses used. CONCLUSIONS: The results from this study revealed that combination therapy with apomine and lovastatin may be a novel treatment strategy for osteosarcoma. Cancer 2012;118:750-

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“…Farnesol is especially interesting in that it has been demonstrated to preferentially induce apoptosis in several transformed cells versus untransformed cells (17,18). Metabolic analyses using labeled choline determined that the addition of farnesol to several cell types in culture resulted in a rapid and dramatic inhibition of PC synthesis, and the metabolic block was due to inhibition at the cholinephosphotransferase step (8,9,19). Farnesol-induced apoptosis could be specifically rescued by exogenous PC or diacylglycerol administration, whereas the addition of other phospholipids was ineffective (8,20).…”

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confidence: 99%

“…Metabolic analyses using labeled choline determined that the addition of farnesol to several cell types in culture resulted in a rapid and dramatic inhibition of PC synthesis, and the metabolic block was due to inhibition at the cholinephosphotransferase step (8,9,19). Farnesol-induced apoptosis could be specifically rescued by exogenous PC or diacylglycerol administration, whereas the addition of other phospholipids was ineffective (8,20). An in vitro enzymatic analysis of cholinephosphotransferase activity present in cell membranes indicated that farnesol inhibited PC synthesis by directly competing with diacylglycerol for binding to the active site of cholinephosphotransferase (9).…”

mentioning

confidence: 99%

“…In a recent study, 31 P NMR spectroscopy was used to study alterations in cellular metabolites upon treatment with a variety of apoptosis inducing drugs as a means of identifying a marker associated with the induction of apoptosis (7). All of the agents tested resulted in an increase in the level of CDP-choline suggesting an inhibition of phosphatidylcholine (PC) 1 synthesis at the cholinephosphotransferase step (8,9).…”

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confidence: 99%

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Uncoupling Farnesol-induced Apoptosis from Its Inhibition of Phosphatidylcholine Synthesis

Wright

Henneberry

Lagace

et al. 2001

Journal of Biological Chemistry

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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.

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Inhibition of Phosphatidylcholine Biosynthesis following Induction of Apoptosis in HL-60 Cells

Cited by 115 publications

References 52 publications

Apoptosis is associated with triacylglycerol accumulation in Jurkat T-cells

Apoptosis is associated with triacylglycerol accumulation in Jurkat T-cells

Synergistic inhibitory effect of apomine and lovastatin on osteosarcoma cell growth

Uncoupling Farnesol-induced Apoptosis from Its Inhibition of Phosphatidylcholine Synthesis

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