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  • Title: Glycosylation of ceramide potentiates cellular resistance to tumor necrosis factor-alpha-induced apoptosis.
    Author: Liu YY, Han TY, Giuliano AE, Ichikawa S, Hirabayashi Y, Cabot MC.
    Journal: Exp Cell Res; 1999 Nov 01; 252(2):464-70. PubMed ID: 10527636.
    Abstract:
    Ceramide, as a second messenger, initiates one of the major signal transduction pathways in tumor necrosis factor-alpha (TNF-alpha)-induced apoptosis. Glucosylceramide synthase (GCS) catalyzes glycosylation of ceramide and produces glucosylceramide. By introduction of the GCS gene, cytotoxic resistance to TNF-alpha has been conferred in human breast cancer cells. MCF-7/GCS-transfected cells expressed 4.1-fold higher levels of GCS activity and exhibited a 15-fold (P < 0.0005) greater EC(50) for TNF-alpha, compared with the parental MCF-7 cell line. DNA fragmentation and DNA synthesis studies showed that TNF-alpha had little influence on the induction of apoptosis or on growth arrest in MCF-7/GCS cells, compared to MCF-7 cells. These studies reveal that TNF-alpha resistance in MCF-7/GCS cells is closely related to ceramide hyperglycosylation, a hallmark of this transfected cell line, and resistance was not aligned with changes in TNF receptor 1 expression. This work demonstrates that GCS, which catalyzes ceramide glycosylation, potentiates cytotoxic resistance to TNF-alpha.
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