Cisplatin resistance significantly affects the survival rate of patients with ovarian cancer. However, the main mechanism underlying cisplatin resistance in ovarian cancer remains unclear.

Methods: Immunohistochemistry was used to determine the expression of OGT, OGA and O-GlcNAc in chemoresistant and chemosensitive ovarian cancer tissues. Functional analyses (in vitro and in vivo) were performed to confirm the role of OGT in cisplatin resistance. Autophagy-related proteins were tested by western blot. Transmission electron microscopy and mRFP-GFP-LC3 adenovirus reporter were used for autophagy flux analysis. Immunoprecipitation assay was utilized to detect protein-protein interactions.

Results: We found that O-GlcNAc and O-GlcNAc transferase (OGT) levels were significantly lower in chemoresistant ovarian cancer tissues than in chemosensitive tissues, whereas O-GlcNAcase (OGA) levels did not differ. The down-regulation of OGT increased cisplatin resistance in ovarian cancer cells but had no effect on the efficacy of paclitaxel. The down-regulation of OGT improved tumor resistance to cisplatin in a mouse xenograft tumor model. OGT knockdown enhanced cisplatin-induced autophagy, which reduced apoptotic cell death induced by cisplatin, and promoted autolysosome formation. A reduction in O-GlcNAcylated SNAP-29 levels caused by the down-regulation of OGT promoted the formation of the SNARE complex and autophagic flux.

Conclusion: Our findings suggest that down-regulation of OGT enhances cisplatin-induced autophagy via SNAP-29, resulting in cisplatin-resistant ovarian cancer. OGT may represent a novel target for overcoming cisplatin resistance in ovarian cancer.

Keywords: autophagy, chemoresistance, OGT, ovarian cancer, SNARE.

顺铂耐药性显着影响卵巢癌患者的生存率。但是，卵巢癌中顺铂耐药的主要机制尚不清楚。

方法：采用免疫组织化学方法检测OGT，OGA和O- GlcNAc在卵巢癌化学性和化学敏感性性组织中的表达。进行功能分析（体外和体内）以确认OGT在顺铂耐药性中的作用。通过蛋白质印迹法检测自噬相关蛋白。透射电镜和mRFP-GFP-LC3腺病毒报告基因用于自噬通量分析。免疫沉淀测定法用于检测蛋白质-蛋白质相互作用。

结果：我们发现，在化学抗性卵巢癌组织中，O -GlcNAc和O -GlcNAc转移酶（OGT）的水平显着低于对化学敏感的组织，而O -GlcNAcase（OGA）的水平没有差异。OGT的下调增加了卵巢癌细胞的顺铂耐药性，但对紫杉醇的疗效没有影响。在小鼠异种移植肿瘤模型中，OGT的下调改善了肿瘤对顺铂的耐药性。OGT组合可增强顺铂诱导的自噬，减少顺铂诱导的凋亡细胞死亡，并促进自溶酶体的形成。减少OOGT下调引起的-GlcNAcylated SNAP-29水平促进了SNARE复合物和自噬通量的形成。

结论：我们的发现表明OGT的下调可通过SNAP-29增强顺铂诱导的自噬，导致顺铂耐药的卵巢癌。OGT可能代表克服卵巢癌中顺铂耐药性的新目标。

关键字：自噬，化学抗药性，OGT，卵巢癌，SNARE。