Liu Xiang, Huang Sihao, Zhu Kuangye, Du Ludi
Department of Breast and Nail Surgery, Quzhou People's Hospital, No. 100 Minjiang Avenue, Kecheng District, Quzhou, 324000, Zhejiang, China.
Biochem Genet. 2025 May 15. doi: 10.1007/s10528-025-11129-9.
Adriamycin (ADR) is a chemotherapy drug for breast cancer, and its resistance is a major obstacle in the clinical treatment of breast cancer. O-GlcNAcylation is a post-translational modification that impacts chemotherapy resistance in cancers. This present study aims to investigate the mechanism of O-GlcNAcylation-mediated ADR resistance in breast cancer. Cell viability, proliferation, and apoptosis were performed to evaluate ADR resistance in breast cancer cells. O-GlcNAcylation, OGA and OGT levels in patients, and breast cancer cells resistant to ADR or not were detected by western blot and quantitative real-time PCR. Glycolysis of ADR-resistant cells was evaluated by measurement of glucose and lactic acid levels, and extracellular acidification rate and oxygen consumption rate. The underlying mechanism was explored by western blot and pathway enrichment analysis. Effects of OGT in vivo were assessed by xenograft tumor model. Results showed that OGT protein and mRNA levels were increased in MCF-7R and BT-549R cells and tumors of ADR-resistant patients with breast cancer. Moreover, O-GlcNAcylation was increased in ADR-resistant breast cancer cells. OGT knockdown inhibited glycolysis and O-GlcNAcylation and protein level of MDM4 at S96 site. Notably, MDM4 overexpression restored glycolysis in MCF-7R and BT-549R cells inhibited by OGT knockdown. Additionally, OGT knockdown inhibited tumor growth in vivo. Collectively, this study demonstrated that OGT promote breast cancer resistant to ADR through facilitating glycolysis in breast cancer cells by O-GlcNAcylation on MDM4. This study may provide a target for overcoming ADR resistance in breast cancer.
阿霉素（ADR）是一种用于治疗乳腺癌的化疗药物，其耐药性是乳腺癌临床治疗中的主要障碍。O-连接的N-乙酰葡糖胺糖基化（O-GlcNAcylation）是一种翻译后修饰，会影响癌症中的化疗耐药性。本研究旨在探讨O-GlcNAcylation介导的乳腺癌对ADR耐药的机制。通过检测细胞活力、增殖和凋亡来评估乳腺癌细胞对ADR的耐药性。采用蛋白质免疫印迹法和定量实时聚合酶链反应检测患者以及对ADR耐药或不耐药的乳腺癌细胞中的O-GlcNAcylation、OGA和OGT水平。通过测量葡萄糖和乳酸水平、细胞外酸化率和氧消耗率来评估ADR耐药细胞的糖酵解情况。通过蛋白质免疫印迹法和通路富集分析探索潜在机制。通过异种移植肿瘤模型评估OGT在体内的作用。结果显示，在MCF-7R和BT-549R细胞以及ADR耐药乳腺癌患者的肿瘤中，OGT蛋白和mRNA水平升高。此外，ADR耐药乳腺癌细胞中的O-GlcNAcylation增加。敲低OGT可抑制糖酵解、O-GlcNAcylation以及MDM4在S96位点的蛋白水平。值得注意的是，MDM4过表达可恢复MCF-7R和BT-549R细胞中因敲低OGT而受到抑制的糖酵解。此外，敲低OGT可在体内抑制肿瘤生长。总的来说，本研究表明OGT通过O-GlcNAcylation修饰MDM4促进乳腺癌细胞的糖酵解，从而促进乳腺癌对ADR产生耐药性。本研究可能为克服乳腺癌对ADR的耐药性提供一个靶点。
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