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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以出现在其他 CRISP 条目中 列出的机构是。 对于中心来说，它不一定是研究者的机构。 癌症干细胞负责肿瘤发生和转移，在化疗过程中存活下来的肿瘤总是表现出对治疗的显着抵抗和侵袭性转移，耐药癌症的这些特性表明存在一种未被识别的干细胞类型，即药物干细胞。我们认为耐药性癌症干细胞 (DR-CSC) 是导致无法治愈的癌症的原因；葡萄糖神经酰胺合酶是调节神经酰胺糖基化的关键酶；化疗对 DR-CSC 形成的表观遗传效应 对人 MCF-7 乳腺癌细胞的癌症干细胞的表征发现，长期低剂量的阿霉素治疗（0.1 µM，超过 10 代）会导致这一结果。增加了侧群细胞的数量 除了具有典型标记 CD44+ 和 CD24- 的乳腺癌干细胞外，还具有一种新型干细胞的特征，具有 MDR1、SSEA-3 和标记。 10月4日，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癌症干细胞的数量（5x105个细胞/小鼠）的接种。所有有肺转移的无胸腺裸鼠，但转染反义GCS基因的细胞(MCF-7-AdrR/asGCS)不能形成肿瘤(10只小鼠/组)。体内研究，低剂量阿霉素治​​疗（0.5 mg/kg/周，21 天）诱导癌症干细胞产生耐药性，然而，针对 GCS 的混合主链寡核苷酸（MBO-asGCS，1 mg/kg/3 天）。 ）治疗减少了癌症干细胞，并且这些细胞对阿霉素敏感。这些初步数据表明，GCS 引起的神经酰胺糖基化与癌症化疗期间 DR-CSC 的形成有关。