促衰老疗法（称为 TIS（治疗诱导衰老））用于治疗结直肠癌 (CRC) 的潜在用途引起了人们的极大兴趣，因为与诱导细胞凋亡所需的剂量相比，它们所需的剂量较低。然而，衰老细胞周期停滞的癌细胞寿命很长，研究揭示了导致肿瘤复发的逃逸机制。为了加深我们对衰老癌细胞生存途径的理解，我们深入研究了己糖胺生物合成途径（HBP）的潜在参与。 HBP 提供 UDP-GlcNAc，O-GlcNAc 转移酶 (OGT) 的底物，可催化 O-GlcNAc 酰化，这是一种与调节多种细胞功能有关的翻译后修饰，在 CRC 中异常升高。在这项研究中，我们证明，在 p53 熟练的结肠癌细胞系 HCT116 和 LS174T 中，低剂量 SN38 或依托泊苷治疗诱导的 TIS 伴随着 GFAT（HBP 的限速酶）、OGT 和O-GlcNAcase (OGA) 表达与 O-GlcNAcylation 水平的轻微降低相关。通过敲低 GFAT 或 OGT 进一步降低 O-GlcNAcylation 水平，可将细胞对亚毒性化疗剂量的反应从衰老转向细胞凋亡，与 DNA 损伤的增强相关。在 HCT116 和 LS174T 细胞以及患者来源的结肠肿瘤模型中，OSMI-4 对 OGT 的药理学抑制支持了这些发现。综上所述，这些结果表明，将 O-GlcNAc 酰化抑制剂与低剂量的常规化疗药物组合可能会减少治疗副作用，同时保持疗效。此外，这种方法可能会增加治疗特异性，因为与正常组织相比，CRC 细胞表现出更高的 O-GlcNAcNAc 水平。© 2024。作者。

The potential use of pro-senescence therapies, known as TIS (Therapy-Induced Senescence), for the treatment of colorectal cancer (CRC) generated significant interest since they require lower doses compared to those required for inducing apoptosis. However, the senescent cell cycle-arrested cancer cells are long-lived, and studies have revealed escape mechanisms contributing to tumor recurrence. To deepen our understanding of the survival pathways used by senescent cancer cells, we delved into the potential involvement of the hexosamine biosynthetic pathway (HBP). HBP provides UDP-GlcNAc, the substrate for O-GlcNAc transferase (OGT), which catalyzes O-GlcNAcylation, a post-translational modification implicated in regulating numerous cellular functions and aberrantly elevated in CRC. In this study, we demonstrated, in the p53-proficient colon cancer cell lines HCT116 and LS174T, that TIS induced by low-dose SN38 or etoposide treatment was accompanied with a decrease of GFAT (the rate limiting enzyme of the HBP), OGT and O-GlcNAcase (OGA) expression correlated with a slight reduction in O-GlcNAcylation levels. Further decreasing this level of O-GlcNAcylation by knocking-down GFAT or OGT redirected the cellular response to subtoxic chemotherapy doses from senescence to apoptosis, in correlation with an enhancement of DNA damages. Pharmacological inhibition of OGT with OSMI-4 in HCT116 and LS174T cells and in a patient-derived colon tumoroid model supported these findings. Taken together, these results suggest that combing O-GlcNAcylation inhibitors to low doses of conventional chemotherapeutic drugs could potentially reduce treatment side effects while preserving efficacy. Furthermore, this approach may increase treatment specificity, as CRC cells exhibit higher O-GlcNAcylation levels compared to normal tissues.© 2024. The Author(s).