GLUCOSYLCERAMIDE SYNTHASE IN A NOVEL TARGET FOR CANCER TREATMENT

葡萄糖神经酰胺合成酶作为癌症治疗的新靶点

• 批准号: 7959471
• 负责人: Yong-Yu Liu
• 金额: $ 7.76万
• 依托单位: LOUISIANA STATE UNIV A&M COL BATON ROUGE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7959471
• 关键词: ABCB1 gene; Biomedical Research; Breast Cancer Cell; CD44 gene; Cells; Ceramide glucosyltransferase; Ceramides; Chemotherapy-Oncologic Procedure; Computer Retrieval of Information on Scientific Projects Database; Data; Dose; Doxorubicin; Drug resistance; Enzymes; Epigenetic Process; Funding; Genes; Grant; Human; Institution; Louisiana; Lung; MCF7 cell; Malignant Neoplasms; Mixed-Backbone Oligonucleotide; Mus; Neoplasm Metastasis; Nude Mice; Population; Property; Research; Research Personnel; Resources; Side; Source; Stem cells; United States National Institutes of Health; cancer stem cell; cancer therapy; chemotherapy; glycosylation; in vivo; malignant breast neoplasm; novel; therapy resistant; treatment duration; tumor; tumorigenesis

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.

该副本是使用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这是调查员的机构。 癌症干细胞负责肿瘤发生和转移。在化学疗法过程中幸存的肿瘤始终表现出对治疗和侵略性转移的继发性。抗药性癌症的这些特性表明存在一种未识别的干细胞类型的耐药性癌症干细胞。我们假设耐药性癌细胞（DR-CSC）是无法治愈的癌症的原因。葡萄糖基酰胺合酶，一种用于神经酰胺糖基化的关键酶，可调节化学疗法对DR-CSC形成形成的表观遗传作用。人类MCF-7乳腺癌细胞的癌症干细胞的表征发现，长期和低剂量的阿霉素治疗（0.1`m，超过10段）因此增加了侧种群细胞的数量。除了典型的CD44+和CD24-标志物，还以MDR1，SSEA-3和OCT-4的标记为特征。将GCS基因引入MCF-7-ADRR细胞中增加，沉默GCS基因减少了这种类型的癌症干细胞的数量。接种耐药的MCF-7-ADRR细胞（5x105细胞/小鼠）在所有肺地裸鼠中形成肿瘤，但是，反义GCS基因转染细胞（MCF-7-ADRR/ASGC）均无法形成肿瘤（10小鼠/组）。在体内研究中，低剂量的阿霉素治疗（0.5 mg/kg/kg/kg/周，21天）诱导抗药性诱导癌症干细胞。然而，混合的骨干寡核苷酸与GC（MBO-ASGC，1 mg/kg/3天）的治疗减少了癌症干细胞，这些细胞对阿霉素敏感。这些初步数据表明，在癌症化学疗法期间，GCS神经酰胺糖基化与DR-CSC形成有关。