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Ablation of dihydroceramide desaturase confers resistance to etoposide-induced apoptosis in vitro.
- Source :
-
PloS one [PLoS One] 2012; Vol. 7 (9), pp. e44042. Date of Electronic Publication: 2012 Sep 11. - Publication Year :
- 2012
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Abstract
- Sphingolipid biosynthesis is potently upregulated by factors associated with cellular stress, including numerous chemotherapeutics, inflammatory cytokines, and glucocorticoids. Dihydroceramide desaturase 1 (Des1), the third enzyme in the highly conserved pathway driving sphingolipid biosynthesis, introduces the 4,5-trans-double bond that typifies most higher-order sphingolipids. Surprisingly, recent studies have shown that certain chemotherapeutics and other drugs inhibit Des1, giving rise to a number of sphingolipids that lack the characteristic double bond. In order to assess the effect of an altered sphingolipid profile (via Des1 inhibition) on cell function, we generated isogenic mouse embryonic fibroblasts lacking both Des1 alleles. Lipidomic profiling revealed that these cells contained higher levels of dihydroceramide than wild-type fibroblasts and that complex sphingolipids were comprised predominantly of the saturated backbone (e.g. sphinganine vs. sphingosine, dihydrosphingomyelin vs. sphingomyelin, etc.). Des1 ablation activated pro-survival and anabolic signaling intermediates (e.g. Akt/PKB, mTOR, MAPK, etc.) and provided protection from apoptosis caused by etoposide, a chemotherapeutic that induces sphingolipid synthesis by upregulating several sphingolipid biosynthesizing enzymes. These data reveal that the double bond present in most sphingolipids has a profound impact on cell survival pathways, and that the manipulation of Des1 could have important effects on apoptosis.
- Subjects :
- Animals
Cell Survival drug effects
Ceramides chemistry
Ceramides metabolism
Cytoprotection drug effects
Down-Regulation drug effects
Embryo, Mammalian cytology
Enzyme Activation drug effects
Extracellular Signal-Regulated MAP Kinases metabolism
Fibroblasts drug effects
MAP Kinase Signaling System drug effects
Membrane Potential, Mitochondrial drug effects
Mice
Mice, Inbred C57BL
Models, Biological
Protein Phosphatase 2 metabolism
Proto-Oncogene Proteins c-akt metabolism
Sphingolipids metabolism
Apoptosis drug effects
Etoposide pharmacology
Fibroblasts cytology
Fibroblasts enzymology
Gene Deletion
Oxidoreductases deficiency
Oxidoreductases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 7
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 22984457
- Full Text :
- https://doi.org/10.1371/journal.pone.0044042