ablation of dihydroceramide desaturase confers resistance to etoposide-induced apoptosis in vitro消融的dihydroceramide desaturase抵抗etoposide-induced体外细胞凋亡.pdfVIP
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ablation of dihydroceramide desaturase confers resistance to etoposide-induced apoptosis in vitro消融的dihydroceramide desaturase抵抗etoposide-induced体外细胞凋亡
Ablation of Dihydroceramide Desaturase Confers
Resistance to Etoposide-Induced Apoptosis In Vitro
1 1,2 3 1 1
Monowarul M. Siddique *, Benjamin T. Bikman , Liping Wang , Li Ying , Erin Reinhardt ,
4 4 1,3
Guanghou Shui , Markus R. Wenk , Scott A. Summers *
1 Program in Cardiovascular and Metabolic Diseases, Duke-National University of Singapore Graduate Medical School, Singapore, Singapore, 2 Department of Physiology
and Developmental Biology, Brigham Young University, Provo, Utah, United States of America, 3 Sarah W. Stedman Nutrition and Metabolism Center, Duke University
Medical Center, Durham, North Carolina, United States of America, 4 Department of Biochemistry, National University of Singapore, Singapore, Singapore
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
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