A role for ceramide glycosylation in resistance to oxaliplatin in colorectal cancer.

Autor: Madigan JP; Center for Molecular Oncology, University of Connecticut Health, Farmington, CT, USA; Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA., Robey RW; Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA., Poprawski JE; Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA., Huang H; Center for Molecular Oncology, University of Connecticut Health, Farmington, CT, USA., Clarke CJ; Department of Medicine and the Stony Brook Cancer Center at Stony Brook, Stony Brook, NY, USA., Gottesman MM; Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA., Cabot MC; Department of Biochemistry and Molecular Biology, Brody School of Medicine and East Carolina Diabetes Institute, East Carolina University, Greenville, NC, USA., Rosenberg DW; Center for Molecular Oncology, University of Connecticut Health, Farmington, CT, USA. Electronic address: rosenberg@uchc.edu.
Jazyk: angličtina
Zdroj: Experimental cell research [Exp Cell Res] 2020 Mar 15; Vol. 388 (2), pp. 111860. Date of Electronic Publication: 2020 Jan 20.
DOI: 10.1016/j.yexcr.2020.111860
Abstrakt: There is growing evidence to support a role for the ceramide-metabolizing enzyme, glucosylceramide synthase (GCS), in resistance to a variety of chemotherapeutic agents. Whether GCS contributes to oxaliplatin resistance in colorectal cancer (CRC) has not yet been determined. We have addressed this potentially important clinical issue by examining GCS function in two panels of oxaliplatin-resistant, isogenic CRC cell lines. Compared to parental cell lines, oxaliplatin-resistant cells have increased expression of GCS protein associated with increased levels of the pro-survival ceramide metabolite, glucosylceramide (GlcCer). Inhibition of GCS expression by RNAi-mediated gene knockdown resulted in a reduction in cellular GlcCer levels, with restored sensitivity to oxaliplatin. Furthermore, oxaliplatin-resistant CRC cells displayed lower ceramide levels both basally and after treatment with oxaliplatin, compared to parental cells. GlcCer, formed by GCS-mediated ceramide glycosylation, is the precursor to a complex array of glycosphingolipids. Differences in cellular levels and species of gangliosides, a family of glycosphingolipids, were also seen between parental and oxaliplatin-resistant CRC cells. Increased Akt activation was also observed in oxaliplatin-resistant CRC cell lines, together with increased expression of the anti-apoptotic protein survivin. Finally, this study shows that GCS protein levels are greatly increased in human CRC specimens, compared to matched, normal colonic mucosa, and that high levels of UGCG gene expression are significantly associated with decreased disease-free survival in colorectal cancer patients. These findings uncover an important cellular role for GCS in oxaliplatin chemosensitivity and may provide a novel cellular target for augmenting chemotherapeutic drug effectiveness in CRC.
Competing Interests: Declaration of competing interest The authors declare no conflicts of interest.
(Copyright © 2020. Published by Elsevier Inc.)
Databáze: MEDLINE
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