期刊
JOURNAL OF PROTEOME RESEARCH
卷 16, 期 10, 页码 3741-3752出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jproteome.7b00430
关键词
anticancer drug; cell metabolism; drug metabolism; fatty acid metabolism; lipid metabolism; lipidomics; mass spectrometry (MS); metabolomics; multivariate statistical analysis; Saccharomyces cerevisiae
资金
- National Sciences and Engineering Research Council (NSERC) of Canada
- Discovery Accelerator Supplement
- American Cancer Society [124268-IRG-78-002-35-IRG]
The nonmetabolizable lysophosphatidylcholine (LysoPC) analogue edelfosine is the prototype of a class of compounds being investigated for their potential as selective chemotherapeutic agents. Edelfosine targets membranes, disturbing cellular homeostasis. Is not clear at this point how membrane alterations are communicated between intracellular e. compartments leading to growth inhibition and eventual cell death. In the present study, a combined metabolomics/lipidomics approach for the unbiased identification of metabolic pathways altered in yeast treated with sublethal OtahnalcAnd concentrations of the LysoPC analogue was employed. Mass spectrometry of polar metabolites, fatty acids, and lipidomic profiling was used to study the effects of edelfosine on yeast metabolism. Amino acid and sugar metabolism, the Krebs cycle, and fatty acid profiles were most disrupted, with polar metabolites and short medium chain fatty acid changes preceding long and very long-chain fatty acid variations. Initial increases in metabolites such as trehalose, proline, and gamma-amino butyric acid with a concomitant decrease in metabolites of the Krebs cycle, citrate and fumarate, are interpreted as a cellular attempt to offset oxidative stress in response to mitochondrial dysfunction induced by the treatment. Notably, alanine, inositol, and myristoleic acid showed a steady increase during the period analyzed (2, 4, and 6 h after treatment). Of importance was the finding that edelfosine induced significant alterations in neutral glycerolipid metabolism resulting in a significant increase in the signaling lipid diacylglycerol.
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