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: 7609955
• 负责人: Yong-Yu Liu
• 金额: $ 5.36万
• 依托单位: LOUISIANA STATE UNIV A&M COL BATON ROUGE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7609955
• 关键词: Adopted; American; Antineoplastic Agents; Antisense Oligonucleotides; Apoptosis; Arts; Biological; Cancer cell line; Cell Line; Ceramide glucosyltransferase; Ceramides; Colon Carcinoma; Computer Retrieval of Information on Scientific Projects Database; Doxorubicin; Drug resistance; Epithelium; Failure; Funding; Gene Expression; Generations; Genes; Glucosylceramides; Grant; In complete remission; Institution; Malignant Neoplasms; Malignant neoplasm of ovary; Mammary Gland Parenchyma; Messenger RNA; Mixed-Backbone Oligonucleotide; Neoplasm Metastasis; Oligonucleotides; Patients; Pharmaceutical Preparations; Phosphorothioate Oligonucleotide; Positive Lymph Node; Process; Protein Overexpression; Research; Research Personnel; Resistance; Resources; Sampling; Source; Technology; Transfection; United States National Institutes of Health; Work; base; cancer cell; cancer therapy; chemotherapy; glycosylation; improved; in vivo; leukemia; locked nucleic acid; malignant breast neoplasm; melanoma; novel; response; uptake

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. More than 500,000 Americans die every year from cancer, mostly due to a failure at their chemotherapy. Drug-resistance of cancer cells is the biological basis of chemotherapy failure. Improvement of cancer treatment requires adopting the state-of-art technologies to identify target for the reversal of drug-resistance. Glucosylceramide synthase catalyzes ceramide glycosylation, converting ceramide into glucosylceramide. This process deactivates ceramideinduced apoptosis which is involved in the action of anticancer drugs. Our previous works showed that enforced GCS overexpression conferred cancer cells resistance to anticancer drugs, and disrupting GCS gene expression with antisense gene transfection reversed drug resistance via enhancing drug-uptake and sensitizing apoptosis. It is hypothesized that GCS is a potential target for cancer treatment. Recently, we found that GCS overexpression is detected in drug-resistant cell lines including breast cancer, ovarian cancer, colon cancer, melanoma and epithelia cancer. Suppressing GCS expression by using antisense oligonucleotide reversed doxorubicin-resistance in these cancer cell lines. GCS overexpression was detected in more than 70% of metastasis of breast cancer, not detected in fibroplasias, compared to normal breast tissues. GCS overexpression is detected in 87% lymph nodes positive, and 77% ERpositive breast cancer samples. In chemotherapy of patients with leukemia, GCS mRNA levels in non-response group are 2.4-fold higher than that in complete-response group. Suppressing GCS gene by phosphorothioate oligonucleotide selectively sensitizes breast cancer cellsdoxorubicin. Currently, we are examining the second generation of oligonucleotides, including mixed-backbone oligonucleotide, locked nucleic acid, aiming to develop an effective agent to reverse drug-resistance and improve chemotherapy in vivo.

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。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 每年有超过 50 万美国人死于癌症，其中大部分是由于化疗失败。癌细胞的耐药性是化疗失败的生物学基础。改善癌症治疗需要采用最先进的技术来确定逆转耐药性的目标。葡萄糖神经酰胺合酶催化神经酰胺糖基化，将神经酰胺转化为葡萄糖神经酰胺。该过程使神经酰胺诱导的细胞凋亡失活，而神经酰胺诱导的细胞凋亡参与抗癌药物的作用。我们之前的工作表明，强制GCS过度表达会赋予癌细胞对抗癌药物的耐药性，而通过反义基因转染破坏GCS基因表达，可以通过增强药物摄取和敏化细胞凋亡来逆转耐药性。据推测，GCS 是癌症治疗的潜在靶点。最近，我们发现在乳腺癌、卵巢癌、结肠癌、黑色素瘤和上皮癌等耐药细胞系中检测到GCS过度表达。使用反义寡核苷酸抑制 GCS 表达可逆转这些癌细胞系中的阿霉素耐药性。与正常乳腺组织相比，GCS 过度表达在超过 70% 的乳腺癌转移中检测到，而在纤维组织中未检测到。在 87% 的淋巴结阳性和 77% 的 ER 阳性乳腺癌样本中检测到 GCS 过度表达。白血病患者化疗中，无反应组GCS mRNA水平比完全反应组高2.4倍。通过硫代磷酸酯寡核苷酸抑制GCS基因选择性地使乳腺癌细胞阿霉素敏感。目前，我们正在研究第二代寡核苷酸，包括混合主链寡核苷酸、锁核酸，旨在开发一种有效的药物来逆转耐药性并改善体内化疗。