BK21 FOUR KNU Creative BioResearch Group, School of Life Sciences, Kyungpook National University, Daegu 41566, Korea.
Department of Biomedical Science and Research Institute of Bioscience and Biotechnology, Hallym University, Chuncheon 24252, Korea.
Int J Mol Sci. 2021 Oct 14;22(20):11073. doi: 10.3390/ijms222011073.
Levels of O-GlcNAc transferase (OGT) and hyper-O-GlcNAcylation expression levels are associated with cancer pathogenesis. This study aimed to find conditions that maximize the therapeutic effect of cancer and minimize tissue damage by combining an OGT inhibitor (OSMI-1) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). We found that OSMI-1 treatment in HCT116 human colon cancer cells has a potent synergistic effect on TRAIL-induced apoptosis signaling. Interestingly, OSMI-1 significantly increased TRAIL-mediated apoptosis by increasing the expression of the cell surface receptor DR5. ROS-induced endoplasmic reticulum (ER) stress by OSMI-1 not only upregulated CHOP-DR5 signaling but also activated Jun-N-terminal kinase (JNK), resulting in a decrease in Bcl2 and the release of cytochrome c from mitochondria. TRAIL induced the activation of NF-κB and played a role in resistance as an antiapoptotic factor. During this process, O-GlcNAcylation of IκB kinase (IKK) and IκBα degradation occurred, followed by translocation of p65 into the nucleus. However, combination treatment with OSMI-1 counteracted the effect of TRAIL-mediated NF-κB signaling, resulting in a more synergistic effect on apoptosis. Therefore, the combined treatment of OSMI-1 and TRAIL synergistically increased TRAIL-induced apoptosis through caspase-8 activation. Conclusively, OSMI-1 potentially sensitizes TRAIL-induced cell death in HCT116 cells through the blockade of NF-κB signaling and activation of apoptosis through ER stress response.
O-连接的 N-乙酰氨基葡萄糖转移酶（OGT）和高 O-GlcNAc 化表达水平与癌症发病机制有关。本研究旨在通过联合使用 OGT 抑制剂（OSMI-1）和肿瘤坏死因子相关凋亡诱导配体（TRAIL），找到最大限度地提高癌症治疗效果和最小化组织损伤的条件。我们发现，OSMI-1 处理 HCT116 人结肠癌细胞与 TRAIL 诱导的细胞凋亡信号具有很强的协同作用。有趣的是，OSMI-1 通过增加细胞表面受体 DR5 的表达，显著增加了 TRAIL 介导的细胞凋亡。OSMI-1 通过诱导活性氧（ROS）引起内质网（ER）应激，不仅上调 CHOP-DR5 信号，还激活 Jun-N-末端激酶（JNK），导致 Bcl2 减少和细胞色素 c 从线粒体释放。TRAIL 诱导 NF-κB 的激活，并作为一种抗凋亡因子发挥作用以抵抗凋亡。在此过程中，IKK 和 IκBα 的 O-GlcNAc 化发生，随后 p65 易位到细胞核。然而，与 OSMI-1 联合治疗拮抗了 TRAIL 介导的 NF-κB 信号，导致凋亡的协同作用更显著。因此，OSMI-1 和 TRAIL 的联合治疗通过 caspase-8 的激活协同增加 TRAIL 诱导的细胞凋亡。综上所述，OSMI-1 通过阻断 NF-κB 信号和通过 ER 应激反应激活凋亡，可能使 HCT116 细胞对 TRAIL 诱导的细胞死亡敏感。
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