Work

Down-regulation of OGT promotes cisplatin resistance by inducing autophagy in ovarian cancer

Year: 2018

Type: article

Abstract: 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.

Source: Theranostics

DOI: 10.7150/thno.27806