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Antimicrobial Agents and Chemotherapy, June 2009, p. 2392-2401, Vol. 53, No. 6
0066-4804/09/$08.00+0 doi:10.1128/AAC.01551-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
Farnesol-Induced Apoptosis in Candida albicans
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Mark E. Shirtliff,1,2,#
Bastiaan P. Krom,3,#
Roelien A. M. Meijering,3
Brian M. Peters,4
Jingsong Zhu,5
Mark A. Scheper,5
Megan L. Harris,1 and
Mary Ann Jabra-Rizk5,6*
Department of Microbial Pathogenesis, Dental School, University of Maryland, Baltimore, Maryland,1 Department of Microbiology and Immunology, School of Medicine, University of Maryland, Baltimore, Maryland,2 Department of Biomedical Engineering, University Medical Center Groningen and University of Groningen, Groningen, Netherlands,3 Graduate Program in Life Sciences, Microbiology and Immunology Program, School of Medicine, University of Maryland, Baltimore, Maryland,4 Department of Oncology and Diagnostic Sciences, Dental School, University of Maryland, Baltimore, Maryland,5 Department of Pathology, School of Medicine, University of Maryland, Baltimore, Maryland6
Received 20 November 2008/ Returned for modification 12 December 2008/ Accepted 28 March 2009
Farnesol, a precursor in the isoprenoid/sterol pathway, was recently identified as a quorum-sensing molecule produced by the fungal pathogen Candida albicans. Farnesol is involved in the inhibition of germination and biofilm formation by C. albicans and can be cytotoxic at certain concentrations. In addition, we have shown that farnesol can trigger apoptosis in mammalian cells via the classical apoptotic pathways. In order to elucidate the mechanism behind farnesol cytotoxicity in C. albicans, the response to farnesol was investigated, using proteomic analysis. Global protein expression profiles demonstrated significant changes in protein expression resulting from farnesol exposure. Among the downregulated proteins were those involved in metabolism, glycolysis, protein synthesis, and mitochondrial electron transport and the respiratory chain, whereas proteins involved in folding, protection against environmental and oxidative stress, actin cytoskeleton reorganization, and apoptosis were upregulated. Cellular changes that accompany apoptosis (regulated cell death) were further analyzed using fluorescent microscopy and gene expression analysis. The results indicated reactive oxygen species accumulation, mitochondrial degradation, and positive terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) in the farnesol-exposed cells concurrent with increased expression of antioxidant-encoding and drug response genes. More importantly, the results demonstrated farnesol-induced upregulation of the caspase gene MCA1 and the intracellular presence of activated caspases. In conclusion, this study demonstrated that farnesol promotes apoptosis in C. albicans through caspase activation, implying an important physiological role for farnesol in the fungal cell life cycle with important implications for adaptation and survival.
* Corresponding author. Mailing address: Department of Oncology and Diagnostic Sciences, Dental School, University of Maryland, 650 W. Baltimore Street, 7 N, Room 2753, Baltimore, MD 21201. Phone: (410) 708-0508. Fax: (410) 706-0519. E-mail: mrizk{at}umaryland.edu
Published ahead of print on 13 April 2009.
Supplemental material for this article may be found at http://aac.asm.org/.
# Both authors contributed equally.
Antimicrobial Agents and Chemotherapy, June 2009, p. 2392-2401, Vol. 53, No. 6
0066-4804/09/$08.00+0 doi:10.1128/AAC.01551-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
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