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Theranostics 2018; 8(19):5200-5212. doi:10.7150/thno.27806 This issue Cite

Research Paper

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

Fuxing Zhou^1#, Xiaoshan Yang^2#, Hang Zhao^3#, Yu Liu¹, Yang Feng⁴, Rui An⁵, Xiaohui Lv¹, Jia Li^1✉, Biliang Chen^1✉

1. Department of Gynecology and Obstetrics, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China;
2. State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi 710032, China;
3. Department of Pharmacy, the 456th Hospital of the People's Liberation Army, Jinan Shandong 250031, China;
4. Department of Traditional Chinese Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China;
5. Department of Radiology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
^#These authors contributed equally to this work.

✉ Corresponding author: Biliang Chen, Email: cblxjhedu.cn; Jia Li, Email: lijia219net.

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.

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

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