Glucosylceramide Synthase

Ceramide glucosyltransferase (or glucosylceramide synthase) is a glucosyltransferase enzyme involved in the production of glucocerebroside

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Background


Glucosylceramide synthase (GCS) is a limiting enzyme that catalyzes the first step in glycosphingolipid synthesis. A glucose residue is transferred from UDP-glucose to ceramide by GCS to produceglucosylceramide. Enhanced GCS activity or ceramide glycosylation can lead to multidrug resistance (MDR) in breast cancer cells. GSLs are essential for maintenance and formation of stem cells, as knock down of GCS induces apoptosis of embryonic stem cells and stops embryo development in mice. The primary breast cancer cell lines comprise a small population of BCSCs and can be used as source for the study of BCSCs. In the present study, we showed that GCS is involved in the maintenance and formation of BCSCs in drug resistant breast cancer cells. Silencing GCS using mixed back-bone oligonucleotide (MBO-asGCS) significantly reduced the BCSCs in drug-resistant breast cancer cells and sensitized these cells to the chemotherapy. In addition, silencing of GCS in MCF-7/Dox cells by MBO-asGCS significantly retard tumorigenesis in athymic nude mice while the BCSCs enriched MCF-7/Dox cells grew aggressively. These results demonstrated that ceramide glycosylation is involved in the maintenance and formation of BCSCs. Silencing GCS by MBO-asGCS reduces BCSCs chemotherapy and prevents tumor formation.

Chemotherapy remains a standard treatment for patients with metastatic cancers. However, multidrug resistance (MDR) often occurs in more than 50% of patients with cancers during the course of chemotherapy, ultimately resulting in treatment failures. Overexpression of genes that modulate drug action, cell proliferation and apoptosis is the cornerstone for MDR. Studies indicated that glucosylceramide synthase (GCS) is a gene for drug resistance in cancer cells. GCS enzyme converts ceramide to glucosylceramide, thereby deactivating ceramide. Ceramide, a lipid second messenger, mediates growth arrest and apoptosis of cells; ceramide-induced apoptosis contributes to the therapeutic efficiencies of anthracyclines, taxanes, Vinca alkaloids, cytokines, and irradiation. Transfection of GCS gene confers cellular resistance to doxorubicin, tumor necrosis factor-a and daunorubicin in various cancer cell lines. GCS overexpression has been identified in MDR cell lines of breast, ovarian, cervical, and colorectal cancers. GCS has been found overexpressed in leukemia patients with poor-response to chemotherapy and GCS overexpression is associated with the prognosis of breast cancer. Furthermore, a number of studies over past decade have demonstrated that inhibition of GCS sensitizes MDR cells to anticancer drugs. Suppressing GCS overexpression using small interfering RNA (siRNA), phosphorothioate antisense oligonucleotide (PS-oligo) and transfection of antisense sequence overcomes MDR in human breast, colon, cervical and ovarian cancer cell lines. Inhibition of GCS enzyme with small molecules, such as D-threo-l-phenyl-2-decanoylamino-3-morpholino-l-propanol (PDMP), sensitizes cancer cells to doxorubicin, paclitaxel and vincristine.

Emerging evidence indicates that ceramide glycosylation is a newly identified mechanism promoting cellular resistance; however, whether GCS directly modulates tumor response to chemotherapy remains to be clarified. Effectively silencing the GCS gene in vivo can determine whether GCS has a role in tumor drug resistance. Mixedbackbone oligonucleotide (MBO), one type of second-generation antisense oligonucleotides, can specifically inhibit the expression of pathogenic genes and has a better safety profile than PS-oligo in vivo.

References:

Gupta, V. (2011). Ceramide Glycosylation by Glucosylceramide Synthase (GCS) and Breast Cancer Stem Cells: A Dissertation Submitted to the Faculty of the University of Louisiana at Monroe in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy in the College of Pharmacy (Pharmacology) (Doctoral dissertation, University of Louisiana at Monroe).

Patwardhan, G. A. (2010). Ceramide Regulates P53 Expression and Apoptosis in Cell Response to Chemotherapy: A Dissertation Submitted to the Faculty of the University of Louisiana at Monroe in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy in the College of Pharmacy (Pharmacology) (Doctoral dissertation, University of Louisiana at Monroe).