MGMT activated by Wnt pathway promotes cisplatin tolerance through inducing slow-cycling cells and nonhomologous end joining in colorectal cancer  

作　　者：Haowei Zhang Qixin Li Xiaolong Guo Hong Wu Chenhao Hu Gaixia Liu Tianyu Yu Xiake Hu Quanpeng Qiu Gang Guo Junjun She Yinnan Chen 

机构地区：[1]Department of General Surgery,The First Affiliated Hospital of Xi'an Jiaotong University,Xi'an,710061,China [2]Center for Gut Microbiome Research,Med-X Institute,The First Affiliated Hospital of Xi'an Jiaotong University,Xi'an,710061,China [3]Department of High Talent,The First Affiliated Hospital of Xi'an Jiaotong University,Xi'an,710061,China

出　　处：《Journal of Pharmaceutical Analysis》2024年第6期863-877,共15页药物分析学报（英文版）

基　　金：supported by grants from the National Natural Science Foundation of China(Grant Nos.:82003807,82173394);the Shaanxi Province Science Foundation,China(Grant No.:2023-GHZD-19);the Medical Foundation-Clinical Integration Program of Xi'an Jiaotong University,China(Grant No.:YXJLRH2022043);the Xi'an Jiaotong University Free Exploration and Innovation-Teacher Project Foundation,China(Grant No.:xzy012023104).

摘　　要：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.

关 键 词：Colorectal cancer MGMT Chemotherapy resistance Slow-cycling cells Nonhomologous end joining Wnt pathway 

分 类 号：R96[医药卫生—药理学]