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Mechanisms of Action: Physiological Effects

Farnesol-Induced Apoptosis in Candida albicans

Mark E. Shirtliff, Bastiaan P. Krom, Roelien A. M. Meijering, Brian M. Peters, Jingsong Zhu, Mark A. Scheper, Megan L. Harris, Mary Ann Jabra-Rizk
Mark E. Shirtliff
1Department of Microbial Pathogenesis, Dental School, University of Maryland, Baltimore, Maryland
2Department of Microbiology and Immunology, School of Medicine, University of Maryland, Baltimore, Maryland
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Bastiaan P. Krom
3Department of Biomedical Engineering, University Medical Center Groningen and University of Groningen, Groningen, Netherlands
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Roelien A. M. Meijering
3Department of Biomedical Engineering, University Medical Center Groningen and University of Groningen, Groningen, Netherlands
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Brian M. Peters
4Graduate Program in Life Sciences, Microbiology and Immunology Program, School of Medicine, University of Maryland, Baltimore, Maryland
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Jingsong Zhu
5Department of Oncology and Diagnostic Sciences, Dental School, University of Maryland, Baltimore, Maryland
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Mark A. Scheper
5Department of Oncology and Diagnostic Sciences, Dental School, University of Maryland, Baltimore, Maryland
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Megan L. Harris
1Department of Microbial Pathogenesis, Dental School, University of Maryland, Baltimore, Maryland
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Mary Ann Jabra-Rizk
5Department of Oncology and Diagnostic Sciences, Dental School, University of Maryland, Baltimore, Maryland
6Department of Pathology, School of Medicine, University of Maryland, Baltimore, Maryland
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  • For correspondence: mrizk@umaryland.edu
DOI: 10.1128/AAC.01551-08
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  • FIG. 1.
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    FIG. 1.

    Percentage of killed C. albicans cells in total of 2 × 107 cells/ml following 24-h exposure to farnesol (0 to 300 μM), as determined by MTS metabolic assay. Error bars indicate standard errors of the means.

  • FIG. 2.
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    FIG. 2.

    Representative two-dimensional gels of extracted proteins from C. albicans grown in the presence of 0 (0F), 40 (40F), or 200 (200F) μM farnesol, demonstrating differential protein expression. Forty-five protein spots (marked with numbered arrows) displayed consistent alterations upon farnesol treatment. Panels A to D represent the corresponding sections marked on the two-dimensional gels. Information on the identities and functions of these spots are listed in Table 2. MW, molecular weight.

  • FIG. 3.
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    FIG. 3.

    Representative confocal scanning laser fluorescence images of farnesol-treated and untreated C. albicans cells, revealing the presence of (A) ROS accumulation, indicated by green fluorescence, and necrotic or dead cells, indicated by red fluorescence; (B) mitochondrial degradation in the farnesol-exposed cells, indicated by green fluorescence, with healthy mitochondria appearing as red aggregates; and (C) activation of intracellular caspases in the farnesol-exposed cells, indicated by green fluorescence. Minimal patchy fluorescence was observed in the cells treated with 40 μM farnesol, with increasing fluorescence seen with increasing concentrations of farnesol. The amount of farnesol is indicated in each panel by a number and the letter “F.” The bar represents 20 μm.

  • FIG. 4.
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    FIG. 4.

    TUNEL assay showing a dose-dependent increase in apoptosis, indicated by appearance of green fluorescence in farnesol-treated C. albicans cells compared to untreated cells. The amount of farnesol is indicated in each panel by a number and the letter “F.” The bar represents 20 μm.

Tables

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  • TABLE 1.

    Primer sequences used in qPCRa

    PrimerSequence (5′→3′)Fragment size (bp)
    ACT1 f1ATCAAGGTATCATGGTTGGTATGG100
    ACT1 r2TGTTCAATTGGGTATCTCAAGGTC100
    RPP2B f3ACTTAGCTGCTTACTTATTGTTAG143
    RPP2B r4GTCTTTACCTTCCAAATCTTTCA143
    MCAI f3AGGGTATAACCAAGGTTACG200
    MCAI r4CAGAAGGTCTATTGTATTGTCC200
    • ↵ a All primers were optimized at 58°C and showed efficiencies between 90 and 110%.

  • TABLE 2.

    Proteins down- or upregulated with farnesola

    Protein regulation and amount of farnesol (μM)Protein spotProtein (gene)FunctionMWpINo. of peptide matches% Protein score/ confidence interval (%)NCBI nr database accession no.
    Downregulation
        402aPutative stress response protein (DDR48)Damage response226024.271110068483600
    2bTranslational elongation factor 1β (TEF1)Protein synthesis24942674.253100 2494267
    5Riboflavin synthase; hypothetical Ca019-11507 (RIB5)Involved in riboflavin synthesis30917.35.88100 68467869
    6Phosphoglycerate mutase; hypothetical CaO19.8522 (GPM1-2)Glycolysis; changes with drug exposure27437.55.7915100 68469783
    7G-beta-like protein; hypothetical Ca019-9606 (ASC1)Unknown23622.16.34100 68487301
    8Similar to mammalian aldo/keto reductase; hypothetical CaO19.6757 (GRE3)Involved in stress response33095.26.177100 68472117
    9Glyceraldehyde-3-phosphate dehydrogenase (TDH1)Glycolysis; changes with drug exposure35926.76.6115100 68472227
    10Enolase; hypothetical Ca019-8025 (ENO)Glycolysis47202.55.5413100 68488457
        20017ATP synthase subunit D; hypothetical CaO19.10301 (ATP7)Mitochondrial; catalyzes ATP synthesis19364.16.198100 68488805
    18NADH:quinone oxidoreductase; hypothetical CaO19.11095 (CQR2)Enzyme complex of the respiratory chain21714.26.515100 68483141
    19Heat shock protein 60 (HSP60)Mitochondrial; involved in proteins imported into the mitochondrion60378.65.2216100 68485963
    20Orthologous to carboxymethylenebutenolidase; hypothetical CaO19.2966 (YDL086W)Hydrolase enzyme28828.45.844100 68468813
    22Glyceraldehyde-3-phosphate dehydrogenase (TDH1-3)Glycolysis35926.76.6118100 68472227
    24Dihydroxy acid dehydratase (ILV3)Mitochondrion; involved in branched amino acid synthesis63462.96.212100 68467901
    26Pyruvate kinase (PYK1)Glycolysis55757.76.5423100 68482226
    27 S-adenosylmethionine synthase; hypothetical CaO19.8272 (SAM2)Methionine metabolism42465.85.6416100 68484437
    Upregulation
        4023Putative mitochondrial aconitate hydratase (ACO1)Tricarboxylic acid cycle84632.75.9624100 68479387
    88Coproporphyrinogen III oxidase (HEM13)Mitochondrion; involved in heme biosynthesis37089.45.6615100 68490312
    89Branched chain amino acid transaminase; hypothetical CaO19.6994 (BAT1)Involved in branched amino acid synthesis408945.8911100 68482781
    90aAlcohol dehydrogenase; hypothetical CaO19.3997 (ADH3)Functions in formaldehyde metabolism46499.68.2619100 68468132
    91Catalase A (CTA1)Reactive oxygen metabolism54945.26.1816100 68474218
    926-Phosphogluconate dehydrogenase; hypothetical CaO19.12491 (GND1)Plays a critical role in protecting cells from oxidative stress57164.16.1419100 68467359
    93Pyruvate decarboxylase (CDC19/PYK1)Glycolysis627505.3918100 68480872
    96Heat shock protein 70; hypothetical CaO19.12447 (SSA1)Molecular chaperone; involved in response to environmental stress704455.0624100 68467277
    97Alanine/arginine aminopeptidase; hypothetical CaO19.12664 (APE2)Protein degradation107584.45.6337100 68491573
    98Heat shock protein 90 homologue; hypothetical CaO19.6515 (HSP90)Molecular chaperone; involved in response to environmental stress80773.24.8128100 68469132
    99aAryl-alcohol dehydrogenase; hypothetical CaO19.1048 (CAD4)Involved in drug resistance39539.76.8416100 6325169
        20057Heat shock protein 90 (HSP90)Molecular chaperone; involved in response to environmental stress23899.44.33163 68475757
    58Putative Rho protein GDP dissociation factor (RDI1)Involved in reorganization of actin cytoskeleton22947.95.157100 68465635
    59Putative mitochondrial aconitate dehydrogenase (ACO1)Required for tricarboxylic acid cycle and mitochondrial genome maintenance84632.75.9628100 68479387
    60Heat shock protein 60 (HSP60)Mitochondria; oxidative stress response60378.65.22150 68485963
    61Aldose reductase (GRE3)Induced by oxidative stress42602.97.0517100 68470494
    62Coproporphyrinogen III oxidase (HEM13)Mitochondria; involved in heme biosynthesis37089.45.6610100 68490312
    66GTP binding protein; homologue to human Ranp (GSP2)Involved in the maintenance of nuclear organization, RNA processing25148.76.2261006324759
    67Manganese superoxide dismutaseInvolved in defense against ROS14782.78.04246 60760051
    69Mitochondrial 2-enoyl thioester reductaseRequired for respiration and maintenance of mitochondrial function38645.36.361399.99 68486065
    70Putative aspartate aminotransferase (AAT21)Aspartate metabolism49035.38.6117100 68482311
    72Glutathione reductase (GLR1)Oxidative stress57190.17.1810100 55294642
    76Acetyl-CoA hydrolase/transferase (ACH1)Involved in acetyl-CoA pathway58172.56.42898.53 68482646
    78Phosphoglycerate mutase; hypothetical CaO19.8669 (GPM1)Glycolysis30678.17.19599.98 68484809
    80Outer mitochondrial membrane porin; hypothetical CaO19.1042 (POR1)Required for the maintenance of mitochondrial osmotic stability and membrane permeability29748.58.512100 68484582
    81NADH-cytochrome b5 reductase (MCR1)Involved in resistance against oxidative stress33555.68.54148 68490698
    • ↵ a Proteins identified by two-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis and MALDI-TOF MS as being differentially expressed in cells exposed to increasing concentrations of farnesol and unexposed cells. Acetyl-CoA, acetyl coenzyme A.

  • TABLE 3.

    Percentages of cells demonstrating mitochondrial degradation, ROS accumulation, or caspase activationa

    Farnesol conc (μM)Mitochondrial degradationROS accumulationCaspase activity% Dead cells
    0<10<10
    409026513
    10093801320
    20095658435
    • ↵ a Indicate occurrences of apoptosis followed by death upon exposure to increasing concentrations of farnesol.

Additional Files

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  • Supplemental material

    Files in this Data Supplement:

    • Supplemental file 1 - Figure S1 showing gels performed on C. albicans protein samples extracted from cultures grown with or without methanol.
      Zipped PDF document, 200K.
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Farnesol-Induced Apoptosis in Candida albicans
Mark E. Shirtliff, Bastiaan P. Krom, Roelien A. M. Meijering, Brian M. Peters, Jingsong Zhu, Mark A. Scheper, Megan L. Harris, Mary Ann Jabra-Rizk
Antimicrobial Agents and Chemotherapy May 2009, 53 (6) 2392-2401; DOI: 10.1128/AAC.01551-08

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Farnesol-Induced Apoptosis in Candida albicans
Mark E. Shirtliff, Bastiaan P. Krom, Roelien A. M. Meijering, Brian M. Peters, Jingsong Zhu, Mark A. Scheper, Megan L. Harris, Mary Ann Jabra-Rizk
Antimicrobial Agents and Chemotherapy May 2009, 53 (6) 2392-2401; DOI: 10.1128/AAC.01551-08
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KEYWORDS

apoptosis
Candida albicans
farnesol

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