title: Exposure to caspofungin activates Cap and Hog pathways in Candida albicans.
abstract: Caspofungin is a member of the echinocandin group of antifungals and inhibits the activity of beta-glucan synthase thus disrupting cell wall formation and function. While the potent antifungal activity of this agent is well established, this paper analyzed the response of Candida albicans to caspofungin. Exposure of yeast cells to 0.19 microg/ml caspofungin for 1 to 4 h induced nuclear translocation of Cap1p which was confirmed by Western blotting and confocal microscopy. Caspofungin-treated cells demonstrated increased expression of a number of genes associated with the oxidative stress response, including glutathione reductase (GLR1), mitochondrial processing protease (MAS1) and manganese-superoxide dismutase (SOD2) as well as elevated activity of glutathione reductase and superoxide dismutase. Caspofungin treatment also leads to the nuclear localization of Hog1p as visualized by Western blot using anti-phospho-p38 MAPK (Thr180/Tyr182) antibody. This translocation event lead to increased mRNA levels of catalase (CAT1) but not alkyl hydroperoxide reductase (AHP1). The activity of catalase was increased and reached a maximum at 2 h. In addition, pre-exposure of C. albicans to hydrogen peroxide (0.5 mM, 60 min) conferred an increased tolerance to caspofungin. The data presented here highlight the potent antifungal activity of caspofungin and demonstrate that upon exposure to this agent, C. albicans activates the Cap and Hog pathways in an attempt to limit the oxidative and osmotic stresses associated with this drug.
authors.affiliation: Medical Mycology Unit, Department of Biology, National Instiute for Cellular Biotechnology, NUI Maynooth, Co. Kildare, Ireland.
authors.forename: Judy
authors.initials: J
authors.lastname: Kelly
authors.forename: Raymond
authors.initials: R
authors.lastname: Rowan
authors.forename: Malachy
authors.initials: M
authors.lastname: McCann
authors.forename: Kevin
authors.initials: K
authors.lastname: Kavanagh
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D002176:Candida albicans / Q000187:drug effects*; D000077336:Caspofungin; D002374:Catalase / Q000235:genetics / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D054714:Echinocandins / Q000494:pharmacology*; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D005980:Glutathione Reductase / Q000378:metabolism; D055666:Lipopeptides; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D021381:Protein Transport / Q000187:drug effects; D012331:RNA, Fungal / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: C412447:AP1 protein, Candida albicans; D000935:Antifungal Agents; D050976:Basic-Leucine Zipper Transcription Factors; D054714:Echinocandins; D005656:Fungal Proteins; D055666:Lipopeptides; D012331:RNA, Fungal; D012333:RNA, Messenger; D002374:Catalase; D013482:Superoxide Dismutase; D005980:Glutathione Reductase; D020928:Mitogen-Activated Protein Kinases; D000077336:Caspofungin