Enhanced apoptosis through farnesol inhibition of phospholipase D signal transduction

Taylor, Marcia; MacDonald, Kendra; Morris, Andrew J.; McMaster, Christopher R.

doi:10.1111/j.1742-4658.2005.04914.x

Cited by 19 publications

(25 citation statements)

References 48 publications

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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%

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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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Section: Discussionmentioning

confidence: 99%

“…Cells were exposed to 5 lM DTX, 1 nM DTX, or the vehicle (0.5% DMSO) for 6,12,16,24,36,48,72, and 96 h. After each treatment and before analysis, cells were washed twice with PBS (100 ll per well or 10-20 ml per flask) to remove detached and dead cells. The pH of each medium was measured.…”

Section: Cell Treatmentmentioning

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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“…4 Therefore, generation of ROS by FOH may result in the activation of the ERK1/2 pathway and subsequently trigger the ER stress response. However, activation of the ERK1/2 pathway might be related to other actions of FOH, including inhibition of the CDP-choline pathway (5,20,21,48) and inhibition of phospholipase D (22) or HMG CoA reductase activity (6). Future studies have to provide insight into the mechanism by which FOH activates the MEK-ERK pathway.…”

Section: Discussionmentioning

confidence: 99%

“…Isoprenoids have been reported to inhibit posttranslational protein prenylation (19) whereas other studies have shown that FOH is a potent inhibitor of the CDP-choline pathway (5,20,21). Other effects include inhibition of phospholipase D (22), inhibition of 3-hydroxy-3-methylglutaryl CoA reductase (HMG CoA reductase) activity (6), generation of reactive oxygen species (ROS; refs. 23,24), and disorganization of the cytoskeleton (4).…”

Section: Introductionmentioning

confidence: 99%

Farnesol-Induced Apoptosis in Human Lung Carcinoma Cells Is Coupled to the Endoplasmic Reticulum Stress Response

Joo¹,

Liao²,

et al. 2007

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Farnesol (FOH) and other isoprenoid alcohols induce apoptosis in various carcinoma cells and inhibit tumorigenesis in several in vivo models. However, the mechanisms by which they mediate their effects are not yet fully understood. In this study, we show that FOH is an effective inducer of apoptosis in several lung carcinoma cells, including H460. This induction is associated with activation of several caspases and cleavage of poly(ADP-ribose) polymerase (PARP). To obtain insight into the mechanism involved in FOH-induced apoptosis, we compared the gene expression profiles of FOH-treated and control H460 cells by microarray analysis. This analysis revealed that many genes implicated in endoplasmic reticulum (ER) stress signaling, including ATF3, DDIT3, HERPUD1, HSPA5, XBP1, PDIA4, and PHLDA1, were highly up-regulated within 4 h of FOH treatment, suggesting that FOH-induced apoptosis involves an ER stress response. This was supported by observations showing that treatment with FOH induces splicing of XBP1 mRNA and phosphorylation of eIF2A. FOH induces activation of several mitogen-activated protein kinase (MAPK) pathways, including p38, MAPK/extracellular signal-regulated kinase (ERK) kinase (MEK)-ERK, and c-jun NH 2 -terminal kinase (JNK). Inhibition of MEK1/2 by U0126 inhibited the induction of ER stress response genes. In addition, knockdown of the MEK1/2 and JNK1/2 expression by short interfering RNA (siRNA) effectively inhibited the cleavage of caspase-3 and PARP and apoptosis induced by FOH. However, only MEK1/2 siRNAs inhibited the induction of ER stress-related genes, XBP1 mRNA splicing, and eIF2A phosphorylation. Our results show that FOH-induced apoptosis is coupled to ER stress and that activation of MEK1/2 is an early upstream event in the FOH-induced ER stress signaling cascade. [Cancer Res 2007;67(16):7929-36]

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“…albicans e A. nidulans (Voziyan et al, 1995;Yang e Kazanietz, 2003;Taylor et al, 2005;Fairn et al, 2007;Uppuluri et al, 2007;Savoldi et al, 2008;Román et al, 2009). A expressão constitutiva de Pkc1 leva a resistência de S. cerevisiae frente à presença de farnesol, possivelmente pela atividade na regulação da produção de espécies reativas de oxigênio (EROs) na cadeia de transporte de elétrons da mitocôndria (Fairn et al, 2007).…”

Section: -Peptídeo Sinal E Via Secretóriaunclassified

Caracterização funcional do gene codificador de uma proteína com peptídeo sinal, masA, de Aspergillus fumigatus

Cocio¹

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El gen MAS1/GAS2, conocido como "Magnaporthe Apressoria Specific", se identificó como altamente expresado durante la formación de la appressorium fito patógena hongo filamentoso Magnaporthe grisea. En Aspergillus fumigatus, hongo saprofito oportunista, se identificó masA gen ortólogo de MAS1/GAS2 como upregulated en un análisis de transcriptómica expuesto a voriconazol y anidulafungina, antifúngicos que afectan la síntesis de ergosterol y la pared celular, respectivamente. En ambos ortólogos tener una estructura en el extremo N-terminal de la proteína llamada región del péptido señal. Durante la caracterización fenotípica y funcional de gen masA de A. fumigatus se determinó en un análisis in silico de la presencia de péptido señal en la región N-terminal de la proteína. En la caracterización fenotípica de una cepa de A. fumigatus masA -deletado ningún cambio estructural de conidióforos y su aspecto macromorfológico no fue identificado. La cepa deletado masA caracterización es resistente a voriconazol y farnesol que inhiben la síntesis de ergosterol y una molécula de detección de quórum, respectivamente. Al evaluar el nivel de expresión génica masA contra diferentes clases de drogas foi observado el gen súper se expresa cuando se produce daño en la pared celular y la membrana del ADN, la síntesis de lípidos y ácidos grasos, y el estrés oxidativo. En la presencia de daños en la pared celular fúngica causada por anidulafungina, proteína MasA se encuentra cerca de en la pared celular la punta de la hifa y, además, era capaz de transferir al medio extracelular de la proteína fusionada a ella, GFP. Por lo tanto, posiblemente, MasA participa en la vía secretora del hongo sobre todo en momentos de estrés como la ruptura de la pared celular. La capacidad de secreción natural de los hongos filamentosos se ha explotado en el contexto industrial durante décadas. Indicando para este fin, una posible aplicabilidad para este péptido señal.

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Enhanced apoptosis through farnesol inhibition of phospholipase D signal transduction

Cited by 19 publications

References 48 publications

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

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

Farnesol-Induced Apoptosis in Human Lung Carcinoma Cells Is Coupled to the Endoplasmic Reticulum Stress Response

Caracterização funcional do gene codificador de uma proteína com peptídeo sinal, masA, de Aspergillus fumigatus

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