Glycosylation of Ceramide Potentiates Cellular Resistance to Tumor Necrosis Factor-α-Induced Apoptosis |
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Authors: | Yong-Yu Liu Tie-Yan Han Armando E Giuliano Shinichi Ichikawa Yoshio Hirabayashi Myles C Cabot |
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Institution: | a John Wayne Cancer Institute at Saint John's Health Center, Santa Monica, California, 90404;b Laboratory for Cellular Glycobiology, Institute of Chemical and Physical Research, RIKEN, Saitama, Japan |
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Abstract: | Ceramide, as a second messenger, initiates one of the major signal transduction pathways in tumor necrosis factor-α (TNF-α)-induced apoptosis. Glucosylceramide synthase (GCS) catalyzes glycosylation of ceramide and produces glucosylceramide. By introduction of the GCS gene, cytotoxic resistance to TNF-α 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 EC50 for TNF-α, compared with the parental MCF-7 cell line. DNA fragmentation and DNA synthesis studies showed that TNF-α 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-α 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-α. |
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Keywords: | tumor necrosis factor-α ceramide glycosylation drug resistance breast cancer |
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