School of Life Science and Medicine, Dalian University of Technology, Panjin, China.
School of Life Science and Biotechnology, Dalian University of Technology, Dalian, China.
Cell Death Dis. 2018 May 1;9(5):485. doi: 10.1038/s41419-018-0522-0.
Chemoresistance has become a major obstacle to the success of cancer therapy, but the mechanisms underlying chemoresistance are not yet fully understood. O-GlcNAcylation is a post-translational modification that is regulated by the hexosamine biosynthetic pathway (HBP) and has an important role in a wide range of cellular functions. Here we assessed the role of O-GlcNAcylation in chemoresistance and investigated the underlying cellular mechanisms. The results showed that the HBP has an important role in cancer cell chemoresistance by regulating O-GlcNAcylation. An increase in the levels of O-GlcNAcylation indicates an increased resistance of cancer cells to chemotherapy. Acute treatment with doxorubicin (DOX) or camptothecin (CPT) induced O-GlcNAcylation through HBP activation. In fact, the chemotherapy agents activated the AKT/X-box-binding protein 1 (XBP1) axis and then induced the HBP. Furthermore, the observed elevation of cellular O-GlcNAcylation led to activation of survival signalling pathways and chemoresistance in cancer cells. Finally, suppression of O-GlcNAcylation reduced the resistance of both established and primary cancer cells to chemotherapy. These results provide significant novel insights regarding the important role of the HBP and O-GlcNAcylation in regulating cancer chemoresistance. Thus, O-GlcNAc inhibition might offer a new strategy for improving the efficacy of chemotherapy.
耐药性已成为癌症治疗成功的主要障碍，但耐药性的机制尚不完全清楚。O-连接的 N-乙酰葡萄糖胺（O-GlcNAc）修饰是一种受己糖胺生物合成途径（HBP）调控的翻译后修饰，在广泛的细胞功能中具有重要作用。在这里，我们评估了 O-GlcNAc 修饰在耐药性中的作用，并研究了潜在的细胞机制。结果表明，HBP 通过调控 O-GlcNAc 修饰在癌细胞耐药性中起重要作用。O-GlcNAc 修饰水平的增加表明癌细胞对化疗的耐药性增加。阿霉素（DOX）或喜树碱（CPT）的急性处理通过 HBP 激活诱导 O-GlcNAc 修饰。事实上，化疗药物激活 AKT/X 盒结合蛋白 1（XBP1）轴，然后诱导 HBP。此外，观察到的细胞内 O-GlcNAc 修饰水平的升高导致了存活信号通路的激活和癌细胞的耐药性。最后，抑制 O-GlcNAc 修饰降低了已建立和原发性癌细胞对化疗的耐药性。这些结果为 HBP 和 O-GlcNAc 修饰在调节癌症耐药性方面的重要作用提供了重要的新见解。因此，O-GlcNAc 抑制可能为提高化疗疗效提供新策略。
