Mechanism of Farnesol Cytotoxicity: Further Evidence for the Role of PKC-Dependent Signal Transduction in Farnesol-Induced Apoptotic Cell Death

Voziyan, Paul A.; Haug, Jeffrey S.; Melnykovych, George

doi:10.1006/bbrc.1995.1995

Cited by 70 publications

(60 citation statements)

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“…The presence of serum triggers E ,Efarnesol secretion. Therefore the serum concentration in vivo could enhance the invasive potential due to host cell damage caused by high levels of E ,E -farnesol (Melnykovych et al, 1992;Voziyan et al, 1995). In this context, the resistance state also seems to influence E ,E -farnesoldependent virulence, since fluconazole-resistant isolates secrete less E ,E -farnesol than fluconazole sensitive ones.…”

Section: Discussionmentioning

confidence: 99%

The quorum‐sensing molecule E,E‐farnesol—its variable secretion and its impact on the growth and metabolism of Candida species

Weber

Schulz

Ruhnke

2010

Yeast

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Diseases caused by Candida species are an increasing problem. Candida species are associated with high overall mortality, due to a variety of virulence factors such as the yeast-to-hyphal switch and proteolytic enzymes. The phenomenon of microbial communication known as quorum sensing also seems to play an important role. The main characteristics of the quorum-sensing molecule E ,E -farnesol are well known for C. albicans. The present study focused on two questions. One of them concerned the secretion of E ,E -farnesol by C. albicans and involved a close examination of the effect of the medium (serum) and the origin of the isolates used. The second one dealt with the activity of E ,E -farnesol in non-C. albicans species, such as C. tropicalis and C. parapsilosis, e.g. its impact on biofilm formation and growth. Under serum conditions, C. albicans produced up to 58% more E ,E -farnesol at 37• C than at 30• C. The growth of all isolates was reduced and delayed by the administration of E ,Efarnesol. Of all Candida species, C. tropicalis isolates were most strongly affected by the addition of E ,E -farnesol. Biofilm formation on polystyrene was affected by E ,Efarnesol treatment in all non-C. albicans species and C. albicans. E ,E -farnesol exerts its main effect by altering the metabolic activity and growth inhibition of treated Candida species. The results obtained indicate that the presence of E ,E -farnesol in the environment not only regulates the morphology of the Candida species but also affects its fitness. In this regard, the secretion of E ,E -farnesol might provide an advantage for members of the microbial community.

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Section: Discussionmentioning

confidence: 99%

The quorum‐sensing molecule E,E‐farnesol—its variable secretion and its impact on the growth and metabolism of Candida species

Weber

Schulz

Ruhnke

2010

Yeast

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“…Indeed, it was previously shown by 31 P-NMR spectroscopy that induction of apoptosis by farnesol resulted in increased level of CDPC in favor of CPT blockade and the accumulation of fructose-1,6-bisphosphate, a glycolysis derivative, in favor of glycolysis downregulation. Second, DAG decrease could result from decreased hydrolysis of phospholipids, such as PtC via the inhibition of phospholipase C or D activity, as shown for farnesol cytotoxicity [36,37]. Third, CPT blockade may also be due to a rerouting of DAG through the activation of protein kinase C (PKC) or diacylglycerol kinase (DGK).…”

Section: Discussionmentioning

confidence: 99%

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

Bayet-Robert

Morvan

Chollet

et al. 2009

Breast Cancer Res Treat

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There is growing evidence that docetaxel, a microtubule-targeting agent like the other taxane paclitaxel, induces dual cytotoxicity mechanism according to dose level. Postgenomics screening technologies are now more and more applied to the elucidation of drug response mechanisms. Proton nuclear magnetic resonance spectroscopy-based pharmacometabolomics was here applied to get further insight into the response of human MCF7 breast carcinoma cells to docetaxel at high (clinical, 5 lM) and low (1 nM) doses. The global response to both doses was evaluated by nuclear morphology and DNA content, the latter as an index of cell proliferation and DNA ploidy. High dose provoked long-lasting cell cycle arrest in mitosis during the first 48 h of exposure to treatment and severe decrease in DNA content followed by significant amount of cell death. In contrast, at low dose, no long-lasting cell cycle arrest was observed on micrographies, and DNA content was decreased but less than at high dose (P \ 0.05), without significant cell death. This response was compared to biochemical alteration assessed by pharmacometabolomics. Thirty metabolites were identified and quantified. Metabolite profiling at clinical dose revealed time-dependent disorders in derivatives of glycolysis, lipid metabolism and glutathione metabolism.Comparison between high and low doses was performed at 72 h and showed common traits including the accumulation of cytidinediphosphocholine (95.0 and 96.9, respectively, P \ 0.03), the decrease in phosphatidylcholine (90.3 and 90.2, respectively, P \ 0.03), and gluthathione (90.6 and 90.6, respectively, P \ 0.03). Despite that, significant dosedependent differences were found in 12 of 30 measured metabolites. Among them, the most discriminant metabolites were polyunsaturated fatty acids (ratio of high-to-low dose of 14.8, P \ 0.05), glutamate, myoinositol, and homocysteine (ratio \ 0.4, P \ 0.05). In addition, the mechanism for glutathione decrease was different. At high dose, it resulted from extensive consumption with precursor starvation (glutamate: -89%, P \ 0.05) and increased glutathione S-transferase activity (95, P \ 0.01), whereas at low dose, it resulted from glutathione biosynthesis blockade with homocysteine accumulation (?144%, P \ 0.03) and decreased glutathione S-transferase activity (-70%, P \ 0.01). Altogether, this pharmacometabolomics analysis provides further evidence of the varying cellular responses at high and low doses of docetaxel in MCF7 breast cancer cells. The authors Mathilde Bayet-Robert and Daniel Morvan equally contributed to this work.

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“…If true, a farnesol-mediated process could either interfere with the generation of diacylglycerol produced from PC and/or affect a diacylglycerol target molecule that produces a cell survival signal. Indeed, the diacylglycerol regulated protein kinase C␣ and protein kinase C␤ isoforms have been demonstrated to translocate from their active membrane-bound forms to their storage cytosolic forms upon farnesol administration (36,37). …”

Section: Fig 3 Effect Of Over-expression Of Cept1 On Farnesol-inducmentioning

confidence: 99%

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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Mechanism of Farnesol Cytotoxicity: Further Evidence for the Role of PKC-Dependent Signal Transduction in Farnesol-Induced Apoptotic Cell Death

Cited by 70 publications

References 0 publications

The quorum‐sensing molecule E,E‐farnesol—its variable secretion and its impact on the growth and metabolism of Candida species

The quorum‐sensing molecule E,E‐farnesol—its variable secretion and its impact on the growth and metabolism of Candida species

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

Uncoupling Farnesol-induced Apoptosis from Its Inhibition of Phosphatidylcholine Synthesis

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