Faculty of Pharmacy, Department of Biomedicine and Health Informatics, Silpakorn University, Nakhon Pathom, Thailand.
Faculty of Pharmacy, Bioactives from Natural Resources Research Collaboration for Excellence in Pharmaceutical Sciences (BNEP), Silpakorn University, Nakhon Pathom, Thailand.
PLoS One. 2024 Oct 16;19(10):e0312173. doi: 10.1371/journal.pone.0312173. eCollection 2024.
The upregulation of O-GlcNAc signaling has long been implicated in the development and progression of numerous human malignancies, including colorectal cancer. In this study, we characterized eight colorectal cancer cell lines and one non-cancerous cell line for O-GlcNAc-related profiles such as the expression of OGT, OGA, and total protein O-GlcNAcylation, along with their sensitivity toward OSMI-1 (Os), an OGT inhibitor (OGTi). Indeed, Os dose-dependently suppressed the viability of all colorectal cancer cell lines tested. Among the three O-GlcNAc profiles, our results revealed that Os IC50 exhibited the strongest correlation with total protein O-GlcNAcylation (Pearson Correlation Coefficient r = -0.73), suggesting that total O-GlcNAcylation likely serves as a better predictive marker for OGTi sensitivity than OGT expression levels. Furthermore, we demonstrated that Os exhibited a synergistic relationship with regorafenib (Re). We believed that this synergism could be explained, at least in part, by the observed Re-mediated increase of cellular O-GlcNAcylation, which was counteracted by Os. Finally, we showed that the Os:Re combination suppressed the growth of NCI-H508 tumor spheroids. Overall, our findings highlighted OGTi as a potential anticancer agent that could be used in combination with other molecules to enhance the efficacy while minimizing adverse effects, and identified total cellular O-GlcNAcylation as a potential predictive marker for OGTi sensitivity.
O-GlcNAc 信号的上调长期以来一直与许多人类恶性肿瘤的发展和进展有关，包括结直肠癌。在这项研究中，我们对 8 种结直肠癌细胞系和 1 种非癌细胞系进行了 O-GlcNAc 相关特征的研究，包括 OGT、OGA 和总蛋白 O-GlcNAc 化的表达，以及它们对 OSMI-1（Os）的敏感性，Os 是一种 OGT 抑制剂（OGTi）。事实上，Os 以剂量依赖的方式抑制了所有测试的结直肠癌细胞系的活力。在这三种 O-GlcNAc 特征中，我们的结果表明，Os IC50 与总蛋白 O-GlcNAc 化之间表现出最强的相关性（Pearson 相关系数 r = -0.73），这表明总 O-GlcNAc 化可能比 OGT 表达水平更能作为 OGTi 敏感性的预测标志物。此外，我们证明 Os 与regorafenib（Re）表现出协同关系。我们认为，这种协同作用至少部分可以解释为观察到的 Re 介导的细胞 O-GlcNAc 化增加，而 Os 则拮抗了这种增加。最后，我们表明 Os:Re 联合抑制了 NCI-H508 肿瘤球体的生长。总的来说，我们的研究结果强调了 OGTi 作为一种潜在的抗癌药物的作用，它可以与其他分子联合使用，以提高疗效，同时最大限度地减少不良反应，并确定总细胞 O-GlcNAc 化作为 OGTi 敏感性的潜在预测标志物。
