化疗耐药在结直肠癌（CRC）患者的预后和治疗失败中起着关键作用。顺铂 (DDP) 耐药细胞表现出逃避有毒化疗药物作用的固有能力，其特征是激活慢周期程序和 DNA 修复。在导致 DDP 抗性的因素中，O 6-甲基鸟嘌呤 (O 6-MG)-DNA 甲基转移酶 (MGMT)（一种 DNA 修复酶）发挥着重要作用。在这项研究中，我们阐明了 MGMT 在赋予 CRC DDP 抗性方面的重要作用，阐明了 MGMT 调节作用的潜在机制。我们的研究发现，DDP 抗性癌细胞中 MGMT 显着上调，并且 MGMT 抑制增强了这些细胞对体外和体内 DDP 治疗的敏感性。相反，在癌细胞中，MGMT 过度表达消除了它们对 DDP 治疗的敏感性。从机制上讲，MGMT 和细胞周期蛋白依赖性激酶 1 (CDK1) 之间的相互作用是通过促进 CDK1 泛素化降解来诱导慢周期细胞的。同时，为了实现非同源末端连接，MGMT与XRCC6相互作用以抵抗化疗药物。我们来自 88 名 CRC 患者样本的转录组数据表明，MGMT 表达与 Wnt 信号通路激活相关，并且几种 Wnt 抑制剂可以抑制耐药细胞。总之，我们的结果指出 MGMT 是 CRC 化疗耐药的潜在治疗靶点和预测标志物。© 2024 作者。

Chemotherapy resistance plays a pivotal role in the prognosis and therapeutic failure of patients with colorectal cancer (CRC). Cisplatin (DDP)-resistant cells exhibit an inherent ability to evade the toxic chemotherapeutic drug effects which are characterized by the activation of slow-cycle programs and DNA repair. Among the elements that lead to DDP resistance, O 6-methylguanine (O 6-MG)-DNA-methyltransferase (MGMT), a DNA-repair enzyme, performs a quintessential role. In this study, we clarify the significant involvement of MGMT in conferring DDP resistance in CRC, elucidating the underlying mechanism of the regulatory actions of MGMT. A notable upregulation of MGMT in DDP-resistant cancer cells was found in our study, and MGMT repression amplifies the sensitivity of these cells to DDP treatment in vitro and in vivo. Conversely, in cancer cells, MGMT overexpression abolishes their sensitivity to DDP treatment. Mechanistically, the interaction between MGMT and cyclin dependent kinase 1 (CDK1) inducing slow-cycling cells is attainted via the promotion of ubiquitination degradation of CDK1. Meanwhile, to achieve nonhomologous end joining, MGMT interacts with XRCC6 to resist chemotherapy drugs. Our transcriptome data from samples of 88 patients with CRC suggest that MGMT expression is co-related with the Wnt signaling pathway activation, and several Wnt inhibitors can repress drug-resistant cells. In summary, our results point out that MGMT is a potential therapeutic target and predictive marker of chemoresistance in CRC.© 2024 The Authors.