GLUCOSYLCERAMIDE SYNTHASE IN A NOVEL TARGET FOR CANCER TREATMENT

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 每年有超过50万美国人死于癌症，主要是由于化疗失败。癌细胞的耐药性是化疗失败的生物学基础。癌症治疗的进步需要采用最先进的技术来识别逆转耐药的靶点。葡萄糖神经酰胺合成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。这一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与抗癌药物的作用有关。我们以前的工作表明，GCS的过度表达增强了癌细胞对抗癌药物的耐药性，而反义基因转染破坏了GCS基因的表达，通过促进药物摄取和敏化细胞凋亡来逆转耐药性。假设GCS是癌症治疗的潜在靶点。最近，我们发现GCS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都有过表达。通过使用反义寡核苷酸抑制GCS的表达逆转了这些癌细胞对阿霉素的耐药性。与正常乳腺组织相比，GCS在70%以上的乳腺癌转移灶中检测到过表达，而在纤维组织中未检测到。在87%的淋巴结阳性和77%的ER阳性的乳腺癌样本中检测到GCS过表达。在白血病患者化疗中，无反应组的GCS mRNA水平是完全应答组的2.4倍。硫代寡核苷酸抑制GCS基因选择性增敏乳腺癌细胞阿霉素目前，我们正在研究第二代寡核苷酸，包括混合骨架寡核苷酸、锁定核酸，旨在开发一种有效的逆转耐药药物，提高体内化疗效果。

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.