MGMT activated by Wnt pathway promotes cisplatin tolerance through inducing slow-cycling cells and nonhomologous end joining in colorectal cancerOA
MGMT activated by Wnt pathway promotes cisplatin tolerance through inducing slow-cycling cells and nonhomologous end joining in colorectal cancer
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,O6-methylguanine(O6-MG)-DNA-meth-yltransferase(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 sensi-tivity 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.
Haowei Zhang;Gang Guo;Junjun She;Yinnan Chen;Qixin Li;Xiaolong Guo;Hong Wu;Chenhao Hu;Gaixia Liu;Tianyu Yu;Xiake Hu;Quanpeng Qiu
Department of General Surgery,The First Affiliated Hospital of Xi'an Jiaotong University,Xi'an,710061,China||Center for Gut Microbiome Research,Med-X Institute,The First Affiliated Hospital of Xi'an Jiaotong University,Xi'an,710061,ChinaCenter for Gut Microbiome Research,Med-X Institute,The First Affiliated Hospital of Xi'an Jiaotong University,Xi'an,710061,China||Department of High Talent,The First Affiliated Hospital of Xi'an Jiaotong University,Xi'an,710061,ChinaDepartment of General Surgery,The First Affiliated Hospital of Xi'an Jiaotong University,Xi'an,710061,China||Center for Gut Microbiome Research,Med-X Institute,The First Affiliated Hospital of Xi'an Jiaotong University,Xi'an,710061,China||Department of High Talent,The First Affiliated Hospital of Xi'an Jiaotong University,Xi'an,710061,ChinaCenter for Gut Microbiome Research,Med-X Institute,The First Affiliated Hospital of Xi'an Jiaotong University,Xi'an,710061,ChinaDepartment of General Surgery,The First Affiliated Hospital of Xi'an Jiaotong University,Xi'an,710061,ChinaDepartment of General Surgery,The First Affiliated Hospital of Xi'an Jiaotong University,Xi'an,710061,China||Department of High Talent,The First Affiliated Hospital of Xi'an Jiaotong University,Xi'an,710061,China
Colorectal cancerMGMTChemotherapy resistanceSlow-cycling cellsNonhomologous end joiningWnt pathway
《药物分析学报（英文）》 2024 (006)
863-877 / 15
This work was supported by grants from the National Natural Science Foundation of China(Grant Nos.:82003807 and 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),and the Xi'an Jiaotong University Free Exploration and Innovation-Teacher Project Foundation,China(Grant No.:xzy012023104).The Figures were partly generated using Servier Medical Art,provided by Servier and licensed under a Creative Commons Attribution 3.0 unported license.
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