卵巢癌紫杉醇耐药是临床亟待解决的难题之一，其机制尚不完全明确。申请人前期研究发现敲低磷酸吡哆醇氧化酶（PNPO）后导致G2/M期阻滞和CyclinB1表达升高，因而增加细胞对紫杉醇的敏感性，使PNPO成为潜在的卵巢癌紫杉醇耐药靶标。CyclinB1低表达是紫杉醇耐药的重要诱因，揭示PNPO功能增强导致的紫杉醇耐药主要通过调控CyclinB1发挥作用。鉴于细胞分裂的顺利进行有赖于APC/C介导的CyclinB1的泛素化降解，因此，我们推测PNPO可能通过促进APC/C介导的CyclinB1泛素化而导致紫杉醇耐药。本项目是在原有基础上的深入，进一步明确调控PNPO表达在逆转人卵巢癌紫杉醇耐药中的作用；阐明PNPO促进APC/C介导的CyclinB1泛素化导致紫杉醇耐药的分子机制；并通过检测PNPO在人卵巢癌耐药/敏感组织及血清中的表达，为解决卵巢癌紫杉醇耐药提供理论依据和应用方法。

Ovarian cancer (OC) is the most lethal malignant tumor in female reproductive system. Paclitaxel (PTX) is the first line chemotherapeutic agent of OC. PTX resistance is the major problem need to be resolved in clinic. The mechanism of PTX resistance is not fully understood until now. Our previous study showed that pyridoxine 5’-phosphate oxidase (PNPO) is a candidate molecular marker of PTX resistance. PNPO is overexpressed in the well-established PTX-resistant OC cell line. Downregulation of PNPO expression enhances the sensitivity to PTX treatment against this OC cell line by inducing increased expression of Cyclin B1 and cell cycle arrest in G2/M phase. Cell division depends on the Cyclin B1 ubiquitination regulated by APC/C complex, thus, we hypothesize that PNPO-induced PTX resistance was regulated through APC/C complex guided Cyclin B1 ubiquitination. In this project, we will investigate the effect of PNPO in reversing the PTX resistance using OC cell line and nude mice models. Our goal is to clarify the molecular mechanism of PNPO in PTX resistance and further detect the expression of PNPO in human OC tissues and serum samples. Overall, this project will provide theoretical basis and a new strategy for reversing PTX resistance in OC.