GLUCOSYLCERAMIDE SYNTHASE IN A NOVEL TARGET FOR CANCER TREATMENT

这个子项目是众多研究子项目之一

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.