GLUCOSYLCERAMIDE SYNTHASE IN A NOVEL TARGET FOR CANCER TREATMENT

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cancer stem cell is responsible for tumorigenesis and metastasis. Tumors that are survived during the course of chemotherapy always display a substantial resistance to therapy and aggressive metastasis. These properties of drug-resistant cancers suggest the existence of an unrecognized type of stem cell, drug-resistant cancer stem cell. We hypothesize that drug-resistant cancer stem cell (DR-CSC) is a cause of incurable cancers; glucosylceramide synthase, a key enzyme for ceramide glycosylation, modulates the epigenetic effects of chemotherapy on the formation of DR-CSC formation. Characterization of cancer stem cell from human MCF-7 breast cancer cells found that long-term and low-dose of doxorubicin treatments (0.1 ¿M, more than 10 passages) consequently increased the numbers of side population cells. Addition to breast cancer stem cell with typical markers of CD44+ and CD24-, a new type of stem cell was characterized with markers of MDR1, SSEA-3 and Oct-4. Introducing GCS gene into MCF-7-AdrR cells increased, and silence GCS gene decreased the numbers of this type cancer stem cells. Inoculation of drug-resistant MCF-7-AdrR cells (5x105 cells/mice) formed tumors in all athymic nude mice with lung metastasis, however, antisense GCS gene transfected cells (MCF-7-AdrR/asGCS) could not form tumor (10 mice/group). In vivo study, low-dose of doxorubicin treatment (0.5 mg/kg/week, 21 days) induced cancer stem cells with drug-resistance. However, mixed backbone oligonucleotide against GCS (MBO-asGCS, 1 mg/kg/3-day) treatment decreased cancer stem cells and those cells were sensitive to doxorubicin. These preliminary data indicate that ceramide glycosylation by GCS is associated with DR-CSC formation during cancer chemotherapy.